Pharmaceutical composition promoting defecation

ABSTRACT

The present invention provides a medicament having a gentle but strong defecation-promoting action without causing diarrhea. That is, it provides a defecation-promoting agent comprising a compound having an adenosine A 2 receptor antagonism, preferably an adenosine A 2b  receptor antagonism, or a salt thereof.

This application is a Divisional of co-pending application Ser. No.10/257,091, which, is the national phase under 35 U.S.C. § 371 of PCTInternational Application No. PCT/JP01/03643 which has an Internationalfiling date of April 26, 2001, and which designated the United States ofAmerica, and which PCT application claimed priority under 35 U.S.C. §119(a) on Patent application No. 2000-126489 and 2000-220124 filed inJapan on Apr. 26, 2000 and Jul. 21, 2000, each application beingincorporated by reference.

TECHNICAL FIELD

The present invention relates to a novel pharmaceutical compositionpromoting defecation, and to a novel pyrimidine compound or a saltthereof.

PRIOR ART

Constipation refers to a condition where defecation is difficult orrare, and this is a well-known disease. Known constipation is dividedmainly in to e.g. functional constipation (acute constipation andvarious kinds of chronic constipation (for example, atonic constipation,spastic constipation, dyschezia, rectal constipation, chemicallyinducible constipation etc.)), organic constipation, enteroparalyticileus, IBS, constipation accompanying IBS, constipation accompanyingcongenital digestive tract dysfunction, constipation accompanying ileusetc. In defecation in the normal state, stimulation of rectal mucouswith intestinal contents transferred to the rectum is transmitted to thecentral nerve, thus inducing an inclination for the stool while causingthe bowels and muscles to be reflectively relaxed and contracted(defecating reflex), while constipation occurs due to defecatingfunctions ruined by autonomic nervous dysfunction occurred in digestivetracts, hyper-absorption of water into intestinal tracts, a reduction insecretion of intestinal mucus, motility hindrance, digestivepsychosomatic disease in the digestive organs (for example, irritablebowel syndrome (IBS), a reduction in defecating reflective functions,etc. Many of these obstacles are caused by eating habits, life-style,physical activity, psychogenic background (mental stress, emotionalinstability, etc.). Recently, such constipation is a serious problem inthe fields of nursing and clinical and medical cure. As one of factors,there is a rapid increasing number of old people in the society inrecent years and an increase in old peoples requiring nursing. Patientswith constipation (for example, atonic constipation) attributable toautonomous nervous dysfunction are rapidly increasing. Another factor isan increase in diseases readily causing a reduction in the motilityfunction of digestive tracts. In particular, diabetes is one of seriousdiseases, and is problematic as complications to cause a rapid increasein patients with constipation. This is called symptomatic constipation,and also observed in hypothyroidism, sclerodermia, cerebrovasculardisturbances, depression, spinal disturbances, electrolyteabnormalities, uremia, interstitial lung disease, pulmonary emphysemaand various nerve diseases. In addition to these, there are really manyreports on patients with spastic constipation accompanying IBS observedoften in youths, on patients with chemically inducible constipationinduced by use of morphine in cancer patients, etc.

Prescriptions such as a laxative and an enema are conventionally used inprincipal therapeutic methods. However, these chemicals easily causediarrhea upon administration thereof, give physical and mental sufferingto the patients and nurses, and usually require a long time until theiraction appears, and their action is long-lasting. There is also aproblem that overuse of an enema also causes disappearance of aninclination for the stool. Further, when the patient has high bloodpressure or may have cerebral apoplexy, cerebral infarction, cardiacinfarction etc., there is also the situation where an enema should beused inevitably to prevent such diseases. Accordingly, if there is amedicine gently promoting defecation without generating diarrhea, themedicine can be expected to be very useful and advantageous to manypatients and nurses, and there is demand for providing the medicament.However, a medicine satisfactory in these aspects is still not found.

As to a defecation-promoting agent not causing diarrhea, on one hand,WO94/16702 and Jpn. J. Pharmacol. (68, 119-123 (1995)) have reported “Anagent for treating abnormal dejection comprising as an active ingredienta xanthine derivative which selectively and antagonistically inhibitsadenosine A₁ receptor or a pharmacologically acceptable salt thereof.”

Adenosine is an important regulatory factor involved in manyintracellular metabolisms such as regulation of energy levels and cAMPlevels in the living body, opening and closing calcium channels, andinflow of calcium ions into cells, and its interaction with adenosinereceptors on the surface of a cell is essential for exhibiting thesephysiological activities. Four kinds of receptor subtypes (A₁, A_(2a),A_(2b), A₃) have been identified until now. These subtypes are differentfrom one another in their distribution in tissues; that is, the A₁receptor occurs relatively abundantly in the heart, aorta, bladder etc.,but hardly occurs in the jejunum and in the proximal colon, the A₂areceptor is distributed relatively abundantly in the eyeballs, skeletalmuscles etc., the A_(2b) receptor in the proximal colon, eyeballs, lungetc., and the A₃ receptor in the spleen, uterus, prostate etc. (Br. J.Pharmacol., 118, 1461-1468 (1996)). Adenosine is involved in variousphysiological functions such as platelet agglutination, heart beat,contraction of smooth muscles, inflammations, release ofneurotransmitters, neurotransmission, release of hormones, cellulardifferentiation, growth of cells, death of cells, biosynthesis of DNA,etc., thus suggesting the relationship thereof with central nervediseases, cardiovascular diseases, inflammatory diseases, respiratorydiseases, immune diseases etc., so usefulness of adenosine receptoragonists/antagonists against these diseases is expected. In addition toWO94/16702 supra, the relationship between the adenosine receptors andthe intestinal tracts has been reported in e.g. the followings 1) to 5):

1) An agent for treating abnormal acceleration of intestinal motility,which comprises an adenosine derivative or a pharmacologicallyacceptable salt thereof as an active ingredient (JP-A 6-211669);

2) An adenosine Al receptor-selective antagonist brings about adefecation-promoting action by improving the motility of the intestinaltract via release of acetylcholine in neuroterminal distributed in theintestinal tract (Eur. J. Pharmacol., 264, 91 (1994), Gastroenterology,104, 1420 (1993), Neuroscience, 67, 159 (1995));

3) An adenosine A₂ receptor-selective antagonist had nodefecation-promoting action (Jpn. J. Pharmacol., 68, 119-123 (1995),Eur. J. Pharmacol., 64, 91 (1994));

4) Adenosine agonists NECA and CPA were added at 0.1 to 30 μM to ratdistal colon longitudinal muscles contracted by stimulation withCarbachol, whereby relaxation was observed, and this action wasexhibited more strongly by NECA than CPA and antagonized by 1 μM DPCPXas an adenosine antagonist. The pA2 value (NECA, 6.15 to 6.66; CPA, 6.45to 6.55) of the antagonistic action of DPCPX suggested that thisrelaxing action is mediated by A₂ receptor, and this action was notantagonized by 10 μM CGS21680 (Naunyn-Schmiedeberg's Arch. Pharmacol.,359, 140-146 (1999)); and

5) By adding an adenosine A₁/A₂ agonist NECA or an Al agonist CPA toguinea pig distal colon longitudinal muscles contracted by electricalstimulation, relaxation was observed, while the action of an A_(2a)agonist CGS21680 was very weak. Further, the relaxing action of NECA wasantagonized by DPCPX as Al antagonist and 8-PT as A₁/A₂ antagonist, andthe pA2 value of the antagonistic action of the two and their ratio(DPCPX, 8.8; 8-PT, 6.5) suggested that this relaxing action is mediatedvia A₁ receptor. Further, NECA or CPA at a concentration (100 nM) enoughto relax the contraction of guinea pig colon longitudinal muscles byelectrical stimulation did not exhibit a relaxing action on thecontracting action of the muscles stimulated by acetylcholine. From theforegoing, it was suggested that the A₁ receptor via which the relaxingaction of adenosine on the contraction of guinea pig distal colonlongitudinal muscles stimulated by electrical stimulation is mediated,occurs in presynapses at nerve endings and participates in suppressionof release of acetylcholine. NECA exhibited a relaxing action (EC₅₀;10.4 μM) on the contracting action of guinea pig distal colonlongitudinal muscles stimulated with KCl in the presence oftetrodotoxin, while 1 μM CGS21680 did not act thereon, and CPA actedthereon at a high concentration (EC₅₀; 12.6 μM). Further, DPCPX at aconcentration (1 nM) enough to selectively inhibit the A₁receptor didnot show an antagonistic action, thus indicating that this relaxingaction is not mediated via A₁ receptor. Further, DPCPX at aconcentration (10 nM) enough to inhibit the A_(2b) receptor inhibitedthe relaxing action of NECA and CPA, and comparison between the pA2value (NECA; 6.6, CPA; 7.0) in each case and the case (6.6) of DPCPXhaving the pA2 value (5.7) upon inhibition of the action of NECA by 10μM 8-PT indicated that this inhibitory action is mediated via A_(2b)receptor. These results indicated that the relaxing action of adenosineon the contraction of guinea pig distal colon longitudinal musclesstimulated with KCl in the presence of tetrodotoxin is mediated via theA_(2b) receptor present in the longitudinal muscles. From theseexperimental results, it was suggested that adenosine exhibits arelaxing action via the two different receptors, that is, A₁ receptor inpresynapse and A_(2b) receptor in post synapse in guinea pig distantcolon longitudinal muscles (Br. J. Pharmacol., 129, 871-876 (2000)).

The xanthine derivative not causing diarrhea described in WO94/16702supra is reported to exhibit a defecation-promoting action based on anadenosine Al receptor antagonism via cholinergic nerves (Eur. J.Pharmacol., 264, 91 (1994)). Accordingly, it is considered as clinicalsignificance if a strong defecation-promoting action can be exhibitedvia direct action on the digestive tracts. However, the xanthinederivative exhibits a diuretic action based on an adenosine Al receptorantagonism (JP-A 3-173889), so its use as a defecation-promoting agentshould be significantly limited. This is because assuming its use inpatients with complications with renal diseases or old peoples requiringnursing, it is desired that the balance between the diuretic action anddefecation-promoting action is shifted toward the defecation-promotingaction. From the foregoing, in the treatment of constipation,pharmaceutical preparations promoting defecation gently but stronglywithout causing diarrhea can be expected to be very useful in patientsand nurses. That is, the object of the present invention is to searchfor and find such medicaments.

DISCLOSURE OF THE INVENTION

The present inventors made extensive study in view of the circumstancesdescribed above, and on the basis of literatures on the distribution ofadenosine receptors in the intestinal tracts in humans and rats, inwhich A_(2b) receptor belonging to a subtype of A₂ receptor is reportedto occur particularly abundantly in the colon (Mol. Endocrinol., 6, 384(1992), Mol. Pharmacol., 47, 1126 (1995), Br. J. Pharmacol., 118, 1461(1996)) they established the following new concepts (I) and (II).

(I) The difference in the distribution of adenosine receptors in thecolon is related to the functions of the colon. That is, the A₂receptor, particularly A_(2b) receptor, is involved closely inregulation of the functions of the colon.

(II) As for colon motility involved in the defecation, a compound havingan adenosine A₂ receptor antagonism, particularly a compound having anA_(2b) receptor antagonism, brings about the action of regulating colonmotility via a mechanism different from that of the above-mentionedxanthine derivative (A₁ antagonist).

Then, the present inventors made further extensive study, and a result,they found a compound having an A₂ receptor antagonism, particularly acompound having an A_(2b) receptor antagonism, exhibits a gentle butstrong defecation-promoting action without causing diarrhea, and thepresent invention was thereby completed.

That is, the present invention relates to (1) a defecation-promotingagent comprising a compound having an adenosine A₂ receptor antagonismor a salt thereof, (2) a defecation-promoting agent comprising acompound having an adenosine A_(2b) receptor antagonism or a saltthereof, (3) the defecation-promoting agent according to theabove-mentioned (1) or (2), which is used for treating, preventing orimproving a symptom where defecation is difficult and/or rare, (4) thedefecation-promoting agent according to the above-mentioned (1) or (2),which is an agent for treating, preventing or improving constipation,(5) the defecation-promoting agent according to the above-mentioned (1)or (2), which is an agent for treating, preventing or improvingfunctional constipation, (6) the defecation-promoting agent according tothe above-mentioned (5), wherein the the functional constipation isspastic constipation or atonic constipation, (7) thedefecation-promoting agent according to the above-mentioned (1) or (2),which is an agent for treating, preventing or improving irritable bowelsyndrome or constipation accompanying irritable bowel syndrome, (8) Thedefecation-promoting agent according to the above-mentioned (1) or (2),which is an agent for treating, preventing or improving organicconstipation, constipation accompanying enteroparalytic ileus,constipation accompanying congenital digestive tract dysfunction orconstipation accompanying ileus, (9) the defecation-promoting agentaccording to the above-mentioned (1) or (2), which is for evacuatingintestinal tracts at the time of examination of digestive tracts orbefore and after an operation, (10) the defecation-promoting agentaccording to the above-mentioned (1) or (2), wherein the compound is atleast one compound selected from

-   2-amino-4-(2-furyl)-5-(4-pyridyl)pyrimidine,-   3-n-propylxanthine, theophylline, caffeine,-   1,3-dipropylxanthine, enprophylline,-   1-methyl-3-isobutylxanthine, paraxanthine,-   8-phenyltheophylline, 1,3-diethyl-8-phenylxanthine,-   8-[4-[[[[(2-aminoethyl)amino]carbonyl]methyl]oxy]phenyl]-1,-   3-dipropylxanthine,-   8-[4-[[[methyl-(2-dimethylaminoethyl)-amino]sulfonyl]phenyl]-1,3-dipropylxanthine,-   1,3-dimethyl-8-(p-sulfophenyl)xanthine and-   1,3-dipropyl-8-(p-sulfophenyl)xanthine, (11) use of a compound    having an adenosine A₂ receptor antagonism or a salt thereof for    producing a defecation-promoting agent, (12) use of a compound    having an adenosine A2b receptor antagonism or a salt thereof for    producing a defecation-promoting agent, (13) use of an adenosine A2b    receptor antagonist for producing an agent for treating, preventing    or improving constipation, (14) a compound represented by the    formula:    (wherein A represents a phenyl group, pyridyl group, thienyl group    or furyl group which may be substituted with one or two groups    selected from a halogen atom, a hydroxyl group, a C₁₋₆ alkyl group,    a C₁₋₆ alkoxy group and a C₁₋₆ alkoxy-carbonyl group;

B represents a pyridyl group which may be substituted with one or moregroups selected from a halogen atom, a hydroxyl group, a C₁₋₆ alkylgroup and an amino group;

R¹ represents a hydrogen atom, a morpholinyl group or a grouprepresented by the formula —NR^(1a)R^(1b) (wherein R^(1a) and R^(1b) arethe same as or different from each other and each represents a hydrogenatom, a C₁₋₆ alkyl group, a C₁₋₆ acyl group, a phenyl group or a C₁₋₆alkylsulfonyl group); and

R² represents a hydrogen atom or a group represented by the formula—NR^(2a)R^(2b) (wherein R^(2a) and R^(2b) are the same as or differentfrom each other and each represents a hydrogen atom or a C₁₋₆ alkylgroup),

provided that, in the above definition, the cases where (i) A is a4-fluorophenyl group; B is a 4-pyridyl group; R¹ is an amino group; andR² is a hydrogen atom, and (ii) A is a 4-fluorophenyl group; B is a4-pyridyl group; R¹is an acetamide group; and R² is a hydrogen atom areexcluded) or a salt thereof, (15) a compound represented by the formula:

(wherein A, R¹ and R² have the same meanings as defined in theabove-mentioned (16); and B′ is a 1,2-dihydro-2-pyridinone-4-yl groupwhich may be substituted with one or more groups selected from a halogenatom, a hydroxyl group, a C₁₋₆ alkyl group and an amino group) or a saltthereof, (16) a pharmaceutical composition comprising the compounddescribed in the above-mentioned (14) or (15), or a salt of them, (17)the composition according to the above-mentioned (16), which is anadenosine A_(2b) receptor antagonist, (18) the composition according tothe above-mentioned (16), which is a defecation-promoting agent, (19)the composition according to the above-mentioned (16), which is an agentfor treating, preventing or improving constipation, (20) the compositionaccording to the above-mentioned (16), which is an agent for treating,preventing or improving functional constipation, (21) the compositionaccording to the above-mentioned (20), wherein the functionalconstipation is spastic constipation or atonic constipation, (22) Thecomposition according to the above-mentioned (16), which is an agent fortreating, preventing or improving irritable bowel syndrome orconstipation accompanying irritable bowel syndrome, (23) the compositionaccording to the above-mentioned (16), which is an agent for treating,preventing or improving organic constipation, constipation accompanyingenteroparalytic ileus, constipation accompanying congenital digestivetract dysfunction or constipation accompanying ileus, and (24) thecomposition according to the above-mentioned (16), which is forevacuating intestinal tracts at the time of examination of digestivetracts or before and after an operation.

The present invention provides a method for promoting defecation, byadministering a pharmacologically effective amount of a compound havingan adenosine A₂ receptor antagonism or a salt thereof to a patient, amethod for promoting defecation, by administering a pharmacologicallyeffective amount of a compound having an adenosine A_(2b) receptorantagonism or a salt thereof to a patient, and a method for treating,preventing or improving constipation, by administering apharmacologically effective amount of a compound having an adenosineA_(2b) receptor antagonism or a salt thereof to a patient.

The present invention relates to use of a compound represented by theformula (I) or (II) or a salt of them for producing adefecation-promoting agent, and to use of a compound represented by theformula (I) or (II) or a salt of them for producing an agent fortreating, preventing or improving constipation.

The present invention relates to a method for promoting defecation, byadministering a pharmacologically effective amount of a compoundrepresented by the formula (I) or (II) or a salt of them to a patient,and to a method for treating, preventing or improving constipation, byadministering a pharmacologically effective amount of a compoundrepresented by the formula (I) or (II) or a salt of them to a patient.

Hereinafter, the meanings of symbols, terms, etc. used in the presentspecification are described, and the present invention is described indetail.

In this specification, the “defecation-promoting agent” refers to apharmaceutical composition promoting physiological defecation.

In this specification, the “constipation” refers to conditions wheredefecation is felt to be difficult or is rare, and includes variouskinds of constipation such as functional constipation, organicconstipation, enteroparalytic ileus, IBS, constipation accompanying IBS,constipation accompanying congenital digestive tract dysfunction andconstipation accompanying ileus. Further the “constipation” alsoincludes conditions with some sufferings and difficulties even in asmall amount of defecation. Herein, the functional constipation refersto acute constipation and various kinds of chronic constipation (forexample, atonic constipation, spastic constipation, dyschezia, rectalconstipation, chemically inducible constipation etc.).

In this specification, the “compound” refers to both non-peptidecompound and peptide compound. The “compound” may form a salt, or mayform either an anhydride or a hydrate.

In this specification, the “salt” is not particularly limited insofar asit is a pharmacologically acceptable salt of the compound having an A₂receptor antagonism or the compound having an A_(2b) receptorantagonism, and preferable examples thereof include 1) hydrohalogenicacid salts (for example, hydrofluoride, hydrochloride, hydrobromide andhydroiodide); 2) inorganic acid salts (for example, sulfate, nitrate,perchlorate, phosphate, carbonate and bicarbonate); 3) organiccarboxylic acid salts (for example, acetate, oxalate, maleate, tartrateand fumarate); 4) organic sulfonic acid salts (for example,methanesulfonate, trifluoromethanesulfonate, ethanesulfonate,benzenesulfonate, toluenesulfonate and camphor sulfonate); 5) amino acidsalts (for example, aspartate and glutamate); 6) quaternary amine salts;7) alkali metal salts (for example, sodium salt and potassium salt); and8) alkaline earth metal salts (for example, magnesium salt and calciumsalt).

In this specification, the “antagonism” refers to the action ofinactivating by blocking the interaction of the adenosine receptor withits ligand (adenosine), that is, by blocking the binding of the ligandto the receptor. The “compound having an antagonism” refers to acompound having the action of inactivating by blocking the binding ofthe ligand (adnosine) to the adenosine receptor.

Hereinafter, Test Examples are described to demonstrate that thepharmaceutical composition according to the present invention is usefulas a pharmaceutical composition (referred to hereinafter as“defecation-promoting agent”) promoting defecation (Test Examples 1 to3). The compounds used in the test are compounds represented by theformulae:2-Amino-4-(2-furyl)-5-(4-pyridyl)pyrimidine   Compound I

Compound I is a novel A_(2b) receptor antagonist (Example No. 3) foundby the present inventors. On one hand, KF20274 and KW3902 are known asselective A₁ receptor antagonists, while KW6002 is known as a selectiveA_(2a) receptor antagonist. The ability of these compounds to bind toadenosine receptor subtype and the inhibitory ability thereof are shownbelow (Table 6). KF20274 was produced by a process described in J. Med.Chem., Vol. 35, No. 19, 3578-3581 (1992), KW3902 by a process in J. Med.Chem.,Vol. 35, No.5, 924-930 (1992), and KW6002by a process in Bioorg. &Med. Chem. Lett., Vol. 7, No. 18, 2349-2352 (1997). Test Example 1Inhibitory effect of adenosine A2b receptor antagonist on suppressingaction of NECA on Carbachol-stimulated contraction of colon

(1) Excision of the Colon

The abdomen of a rat under anesthesia with ether was opened, and fromthe rectum to the cecum was excised therefrom and soaked in ice-cooledTyrode solution (containing 136 mM NaCl, 2.7 mM KCl, 0.4 mMNaH₂PO₄.2H₂O, 5.6 mM glucose, 11.9 mM NaHCO₃, 1 mM MgCl₂.6H₂O, 1.8 mMCaCl₂). Surrounding connective tissues were removed, and the intestinaltract was cut at positions apart by 1.5 cm from the rectum and by 3 cmfrom the cecum, to give a colon tract of about 3 cm in full length. Boththe terminals of the colon tract were pinched respectively withSerrefines (trade name) to which a string had been connected, and thecolon tract with the side of the cecum facing upward was immediatelysuspended in a Magnus tube filled with Tyrode solution previously warmedat 37° C., and then equilibrated by bubbling with a gas (O₂/CO₂=95/5).The string connected to the Serrefines (trade name) at the side of thececum was suspended, and the change in the length of the colon tract wasdetected with an amplifier for strain pressure (Nihon KohdenCorporation).

(2) Contraction of the Colon Tract with Carbachol

Carbachol (Sigma) at each concentration diluted 100-fold was addedaccumulatively in a volume of 1/100 to the Magnus tube, and the changein the length of the colon tract was measured, and the length thereof inthe absence of Carbachol was regarded as 0% contraction, and the lengththereof in the presence of 1.44 μM Carbachol was regarded as 100%contraction. In the experiment, 3 samples were used.

(3) Inhibitory Effect of NECA on Carbachol-Stimulated Contraction of theColon Tract

To the colon tract in the presence of 1.44 μM Carbachol in the Magnustube was added accumulatively a volume of 1/100 of NECA (Sigma) diluted100-fold, and the change in the length of the colon tract was measured.Assuming that the length thereof in the absence of Carbachol wasregarded as 0% contraction while the length thereof in the presence of1.44 μM Carbachol was regarded as 100% contraction, the contractionthereof in the presence of NECA was determined. In the experiment, 3samples were used.

(4) Inhibitory Effect of Adenosine Receptor Antagonist on SuppressingAction of NECA on Carbachol-Stimulated Contraction of the Colon Tract

0.3 μM Carbachol and 1 μM NECA were successively added to the colontract, and Compound I, KF20274 or KW6002 diluted 100-fold wasaccumulatively added in a volume of 1/100 to the Magnus tube, and thechange in the length of the colon tract was measured. Assuming that thelength thereof in the presence of 0.3 μM Carbachol and 1 μM NECA wasregarded as 0% contraction while the length thereof in the presence of0.3 μM Carbachol only was regarded as 100% contraction, the contractionin the presence of each of the adenosine receptor antagonists wasdetermined. In the experiment, 3 samples were used.

By stimulation with Carbachol (the above operation 2), the colon tractshowed contraction in a manner dependent on the concentration ofCarbachol (Table 1). When the adenosine receptor agonist NECA was addedthereto (the above operation 3), its inhibitory effect on thecontraction was observed in a manner depending on the concentration ofNECA (Table 2). Carbachol has nicotinic and muscarinic acetylcholinereceptor-stimulating actions in autonomic ganglions and smooth musclesrespectively, so the inhibitory effect of NECA on the contraction couldnot be elucidated only by its action working via nerves distributed insmooth muscles, thus suggesting the possibility of its direct action onsmooth muscles. Further, when each antagonist for adenosine receptor wasadded to this system (the above operation 4), Compound I inhibited thesuppressing effect of NECA on the contraction, in a manner depending onthe concentration of Compound I (Table 3). On one hand, the A₁-selectiveantagonist KF20724 and A_(2a)-selective antagonist KW6002 did not showany inhibitory effect. This indicates that the contraction-suppressingeffect of NECA is not an action mediated via A₁ and A_(2a) receptors,thus suggesting the involvement of A_(2b) receptor. It was thussuggested that adenosine could suppress contraction of the colondirectly via the A_(2b) receptor in colon smooth muscles, and thepresent inventors succeeded in directly demonstrating that the A_(2b)receptor antagonist could antagonize to promote contraction of thecolon. TABLE 1 Contraction (%) Carbachol (μM) Mean Standard Error 0.011.4 1.4 0.04 24.5 10.4 0.14 69.1 5.5 0.44 87.0 2.4 1.44 100.0 0.0

TABLE 2 Contraction (%) NECA (μM) Mean Standard Error 0.1 89.0 3.2 0.475.3 4.9 1.4 63.1 6.8 4.4 59.2 4.6 14.4 54.9 8.9Carbachol 1.44 μM (singly added) = 100%

TABLE 3 Contraction (%) Mean Standard Error Compound I (μM) 0.1 71.536.2 0.4 111.0 51.9 1.4 122.0 53.1 4.4 85.9 35.6 KW20274 (μM) 0.1 −8.24.8 0.4 −26.0 20.7 1.4 −40.0 24.2 4.4 −71.0 35.7 KW6002 (μM) 0.1 5.2 3.40.4 1.1 4.2 1.4 −2.9 3.3 4.4 −3.9 7.8Carbachol 0.3 μM + NECA 1 μM = 0%Carbachol 0.3 μM (singly added) = 100%Test Example 2 Defecation-promoting action of the adenosine A_(2b)receptor antagonist in rat

The present inventors examined and compared the action of the A_(2b)receptor antagonist (Compound I), the A₁-selective antagonistor theA_(2a)-selective antagonist on defecation in rats.

SD IGS rats (6-weeks-old, from Charles River) were placed in cages (3animals/cage) and preliminarily allowed food and water ad libitum andraised for 1 week. On the day of the experiment, their weight wasmeasured, a water-absorbing sheet was placed below each cage, and theanimals were fasted but allowed water ad libitum throughout theexperiment. Three hours after fasting was initiated, the fecal pelletswere recovered from each cage and observed for abnormality before theexperiment, and then the compound suspended or dissolved in 0.5% (W/V)methyl cellulose (MC) was orally administered into each rat in a dose of5 ml/kg. On one hand, 0.5% (W/V) MC only was orally given to the controlgroup. After administering the compound, the rats were returned to thecage provided with a new water-absorbing sheet of known weight, and 180minutes after the administration, the fecal pellets on thewater-absorbing sheet were recovered from each cage, and the externalappearance was observed, and the number of fecal pellets was counted.The number of fecal pellets is expressed per each cage (Table 4). Afterthe fecal pellets were recovered, the water-absorbing sheet was weighed,and the weight determined by subtracting the initial weight of thewater-adsorbing sheet from the weight after the experiment was regardedas the volume of urine and expressed as the volume of urine per 100 g ofthe body weight (Table 4). TABLE 4 The number of Urine Volume CompoundDose fecal pellets/3 rats (g/100 g body weight) Control —  1.00 ± 0.680.89 ± 0.10 Compound I 3 mg/kg 16.33 ± 1.82 0.79 ± 0.09 10 mg/kg  30.00± 2.79 1.23 ± 0.13 KW3902 0.3 mg/kg   10.67 ± 2.08 2.08 ± 0.04 1 mg/kg14.50 ± 1.18 2.15 ± 0.09 3 mg/kg 12.83 ± 1.66 2.01 ± 0.06 KW6002 1 mg/kg 6.67 ± 1.63 0.72 ± 0.07 3 mg/kg  7.00 ± 0.86 0.76 ± 0.05

As shown in Table 4, the A₁-selective receptor antagonist KW3902exhibits a defecation-promoting action, but this action can be seen toreach the maximum in a dose of 1 mg/kg. Further, the A_(2a)-selectivereceptor antagonist KW6002 had a low defecation-promoting action. On onehand, the A_(2b) receptor antagonist Compound I did not cause diarrheaand showed an evidently higher defecation-promoting action than theA₁-selective antagonist KW3902 or the A_(2a)-selective antagonistKW6002. Compound I is a compound also having an antagonistic, inhibitoryaction on A₁ receptor, but this strong defecation-promoting actioncannot be elucidated in terms of the absorption or different dose of thecompound having an antagonistic, inhibitory action on A, receptor. Thisis because compounds having an antagonistic, inhibitory action on A₁receptor are well known to have a diuretic action (J. Pharmacol. Exp.Ther., 266, 200 (1993)), but the A₁-selective antagonist KW3902 has astronger diuretic action than Compound I, while its defecation-promotingaction is weaker than Compound I. On the other hand, Compound I has aweaker diuretic action than the A₁-selective antagonist KW3902, whereasits defecation-promoting action is stronger.

That is, Table 4 shows that the action of Compound I cannot beelucidated only by the antagonistic action on A₁ receptor, and that thestronger defecating action was brought about by adding the antagonistic,inhibitory action on A_(2b) receptor. Test Example 3 Contribution ofinhibition of adenosine A_(2b) receptor to defecation-promoting action

For the purpose of further examination of contribution of theantagonistic inhibitory action of Compound I on A_(2b) receptor to thestrong defecation-promoting action thereof, a combination of theA₁-selective antagonist KW3902 and the A_(2a)-selective antagonistKW6002 was administered and compared with Compound I. Test rats and thecompounds were raised and prepared in the same manner as in Test 1.After administering the compounds, the rats were returned to the cageunder which a new water-absorbing sheet had been installed, and after180 minutes, the fecal pellets on the water-absorbing sheet wererecovered from each cage, and the outward appearance was observed andthe number of fecal pellets was counted. The number of fecal pellets isexpressed per cage (Table 5). TABLE 5 KW6002 The number of Compound Dose(1 mg/kg) fecal pellets/3 rats Control — — 2.50 ± 0.65 Compound I 3mg/kg — 34.00 ± 1.00  KW3902 0 mg/kg + 7.00 ± 1.58 1 mg/kg — 9.00 ± 1.081 mg/kg + 18.25 ± 1.49 

In Test Example 3, the A₁-selective antagonist KW3902 was administeredin a dose enough to exhibit a diuretic action. As shown in Table 5, whenthe A₁-selective antagonist KW3902 and the A_(2a)-selective antagonistKW6002 were simultaneously administered, both their respectivedefecation-promoting actions were brought about. Accordingly, a compoundhaving both an antagonistic action on A₁ receptor and an antagonisticaction on A_(2a) receptor is considered to exhibit a strongerdefecation-promoting action than by a single A₁-selective antagonist.However, their action did not reach the defecation-promoting action ofCompound I as the A_(2b) receptor antagonist. That is, the result inTable 5 shows that the contribution of A_(2b) receptor antagonism isvery important for promotion of defecation.

Comprehensive Discussion

The test revealed that the compound antagonistically inhibiting A_(2b)receptor exhibits a strong defecation-promoting action without causingdiarrhea, and its action is further stronger than that of theA₁-selective antagonist. Accordingly, a pharmaceutical preparationcomprising the compound having an A_(2b) receptor antagonism or a saltthereof is useful as a defecation-promoting agent, and in particular apharmaceutical preparation comprising the A_(2b) receptor antagonist isvery useful. It is therefore evident that the defecation-promoting agentof the invention is useful as an agent for treating, preventing orimproving various kinds of constipation, and can exhibit an excellenteffect as an agent for treating, preventing or improving for examplefunctional constipation (acute constipation and various kinds of chronicconstipation (for example, atonic constipation, spastic constipation,dyschezia, rectal constipation, chemically inducible constipationetc.)), organic constipation, enteroparalytic ileus, IBS, constipationaccompanying IBS, constipation accompanying congenital digestive tractdysfunction, constipation accompanying ileus etc. Further, use of thedefecation-promoting agent of the invention as a pharmaceuticalpreparation is very useful not only for treating, preventing orimproving various kinds of constipation, but also as a chemical forevacuating intestinal tracts at the time of examination of digestivetracts or before and after an operation, as an aid for defecation afteran operation, and as a chemical for promoting defecation afteradministering a contrast medium.

Measurement of the Ability of the Compound to Bind to and Inhibit theReceptors

The ability of the compound to bind to and the ability thereof toinhibit each subtype of adenosine receptor was measured in a knownmethod described below.

1) Measurement of the Ability to Bind to Adenosine A₁ Receptor

A human adenosine A₁ receptor cDNA was expressed in excess in CHOK1cells, and this membrane sample was added at a protein concentration of66.7 μg/ml to, and suspended in, 20 mM HEPES buffer, pH 7.4 (10 mMMgCl₂, 100 mM NaCl). To 0.45 ml of this membrane sample suspension wereadded 0.025 ml of 60 nM tritium-labeled chlorocyclopentyl adenosine(³H—CCPA, from NEN Ltd.) and 0.025 ml test compound. This mixture wasleft at 30° C. for 120 minutes, filtered rapidly under suction through aglass fiber filter (GF/B, from Whatman), and immediately washed twicewith 5 ml of 50 mM water-cooled Tris-HCl buffer. Thereafter, the glassfiber filter was transferred to a vial, a scintillator was addedthereto, and the radioactivity on the filter was measured by a liquidscintillation counter. The inhibition of binding of ³H—CCPA to A₁receptor by the test compound was determined using the followingformula, and from this inhibition, 50% inhibition concentration (IC₅₀)was calculated (the following equation).Inhibition (%)=[1−{binding in the presence of the testcompound-non-specific binding)/(total binding-non-specificbinding)}]×100

In the above formula, the total binding means ³H—CCPA-boundradioactivity in the absence of the test compound; the non-specificbinding means ³H—CCPA-bound radioactivity in the presence of 100 μM RPIA([R]-[1-methyl-2-phenylethyl]adenosine); and the binding in the presenceof the test compound means ³H—CCPA-bound radioactivity in the absence ofthe test compound at predetermined concentrations. The inhibitionconstant (Ki value) in the table was determined from the formula ofCheng-Prusoff.

2) Measurement of the Ability to Bind to Adenosine A_(2a) Receptor

An experiment of inhibition of binding to adenosine A_(2a) receptor wasconducted using a membrane sample (Receptor Biology Inc.) where anadenosine A_(2a) receptor cDNA was expressed in excess. This membranesample was added at a protein concentration of 22.2 μg/ml to, andsuspended in, 20 mM HEPES buffer, pH 7.4 (10 mM MgCl₂ and 100 mM NaCl).To 0.45 ml of this membrane sample suspension were added 0.025 ml of 500nM tritium-labeled2-p-[2-carboxyethyl]phenetylamino-5′-N-ethylarboxyamide adenosine(³H—CGS21680, from NEN) and 0.025 ml test compound. This mixture wasleft at 25° C. for 90 minutes, filtered rapidly under suction through aglass fiber filter (GF/B, from Whatman), and immediately washed twicewith 5 ml of 50 mM water-cooled Tris-HCl buffer. Thereafter, the glassfiber filter was transferred to a vial, a scintillator was addedthereto, and the radioactivity on the filter was measured by a liquidscintillation counter. The inhibition of binding of ³H—CGS21680 toA_(2a) receptor by the test compound was determined using the followingformula, and from this inhibition, 50% inhibition concentration (IC5₀)was calculated.Inhibition (%)=[1−{binding in the presence of the testcompound-nonspecific binding)/(total binding-nonspecific binding)}]×100

In the above formula, the total binding means ³H—CGS21680-boundradioactivity in the absence of the test compound; the nonspecificbinding means ³H—CGS21680-bound radioactivity in the presence of 100 μMRPIA; and the binding in the presence of the test compound means³H—CGS21680-bound radioactivity in the absence of the test compound atpredetermined concentrations. The inhibition constant (Ki value) in thetable was determined from the formula of Cheng-Prusoff.

3) Experiment of Inhibition of NECA-Stimulated Production of cAMP inAdenosine A_(2b) Receptor-Expressing Cells

CHOK1 cells where a human adenosine A_(2b) receptor had been expressedin excess were plated onto a 24-well plate at a density of 1.5×10⁵cells/well, cultured overnight, and used in the experiment. The degreeof inhibitory effect of the test compound on the amount of cAMP producedby stimulation with 30 nM 5′-N-ethylcarboxyamide adenosine (NECA fromSigma) was evaluated in terms of affinity for A_(2b) receptor. That is,the adhering cells were washed twice with 2 ml/well Krebs-Ringer buffersolution (containing0.1%BSA;pH7.4) andpre-incubated for 30 minutes in avolume of 0.5 ml/well. Then, a mixed solution containing NECA and thetest compound was added in a volume of 0.1 ml/well in the presence of aphosphodiesterase inhibitor Ro-20-1724 (a product of RBI). Afterpre-incubation for 15 minutes, the reaction was terminated with 0.1 NHCl in a volume of 300 μl/well. Measurement of intracellular cAMP wascarried out using a cAMP enzyme immunoassay kit produced by Amersham.The inhibition of NECA-stimulated production of cAMP by the testcompound was determined using the following equation: Inhibition(%)=[1−{(amount of cAMP in the coexistence of NECA and the testcompound-amount of cAMP in only the Krebs-Ringer buffersolution)/(amount of cAMP upon stimulation with NECA only-amount of cAMPin only the Krebs-Ringer buffer solution)}]×100

From the inhibition thus determined, 50% inhibition concentration (IC₅₀)was determined.

The results of the experiment of measuring the ability to bind to, andthe ability to inhibit, each receptor are as follows (Table 6). TABLE 6A₁ receptor A_(2a) receptor A_(2b) receptor Test Compound Ki (nM) Ki(nM) IC₅₀ (nM) Compound I 660 112 8.4 KW3902 10 40 126 KW6002 22600 522850

Those skilled in the art to which the present invention belongs canmeasure the ability of any compounds to bind to, or to inhibit, theadenosine receptor subtype thereby identifying a compound having an A₂receptor antagonism and a compound having an A_(2b) receptor antagonism.

Until now, the compounds shown below or a salt thereof (compounds shownin (1) to (27) below) are known as compounds exhibiting an A_(2b)receptor antagonism. The antagonistic action of these known compounds onA_(2b) receptor can be confirmed in the tests described above. Thesecompounds and/or a salt thereof are useful as the active ingredient inthe defecation-promoting pharmaceutical composition according to thepresent invention.

(8) 2,4-Dioxobenzo[g]pteridine

(9) Purine derivatives represented by the formula:

(wherein R¹ means the formula:

(wherein X represents a hydrogen atom, a hydroxyl group, a lower alkylgroup which may have a substituent group, a lower alkoxy group which mayhave a substituent group, an aryl group which may have a substituentgroup, a heteroaryl group which may have a substituent group, an acylgroup which may have a substituent group, an acyloxy group which mayhave a substituent group or an amino group which may have a substituentgroup; and

R⁵ and R⁶ are the same as or different from each other and eachrepresents a hydrogen atom, a lower alkyl group which may have asubstituent group, a saturated or unsaturated C₃₋₈ cycloalkyl groupwhich may have a substituent group, a C₃₋₈ cycloalkyl-C₂₋₆ alkyl groupwhich may have a substituent group, an aryl group which may have asubstituent group, a heteroaryl group which may have a substituentgroup, a carboxyl group which may have a protective group or a 4- to6-memberred ring having at least one heteroatom which may have asubstituent group, or R⁵ and R⁶ together represent an oxygen atom orsulfur atom, or together with the carbon atom to which they bind,represent a ring which may have a heteroatom and a substituent group) or(2) a 5- or 6-memberred aromatic ring which may have a substituent and aheteroatom;

W means a group represented by the formula —CH₂CH₂—, —CH═CH— or —C≡C—;

R² represents a hydrogen atom, a lower alkyl group which may have asubstituent group, a hydroxyl group or the formula —NR⁷R⁸ (wherein R⁷and R⁸ are the same as or different from each other and represents ahydrogen atom, a hydroxyl group, a C₁₋₆ alkyl group which may have asubstituent group, an acyl group which may have a substituent group, aC₃₋₈ cycloalkyl group which may have a substituent group, an aryl groupwhich may have a substituent group or a heteroaryl group which may havea substituent group, or R⁷ and R⁸ together with the nitrogen atom towhich they bind form a saturated ring which may have a heteroatom or asubstituent group);

R³represents a hydrogen atom, a C₃₋₈ cycloalkyl group which may have asubstituent group, an aryl group which may have a substituent group, aheteroaryl group which may have a substituent group or a C₂₋₆ alkenylgroup which may have a substituent group; and

R⁴ represents a hydrogen atom, a lower alkyl group which may have asubstituent group, a C₃₋₈ cycloalkyl group which may have a substituentgroup, an aryl group which may have a substituent group, a heteroarylgroup which may have a substituent group, a C₂₋₆ alkenyl group which mayhave a substituent group, a C₂₋₆ alkynyl group which may have asubstituent group or a cyclic ether which may have a substituent group,

provided that the case where 1) W is —CH₂CH₂—; and X is a hydrogen atomor an alkyl group and the case where 2) W is —C≡C—; R³ is a hydrogenatom; and R⁴ is a cyclic ether which may have a substituent group areexcluded), a pharmaceutically acceptable salt thereof or a hydrate ofthem (JP-A 11-263789).

(10) Purine compounds represented by the formula:

(wherein R¹ represents (1) a hydrogen atom, (2) a hydroxyl group, (3) ahalogen atom, (4) a C₁₋₈ alkyl group which may have a substituent groupor (5) the formula —NR⁴R⁵ (wherein R⁴ and R⁵ are the same as ordifferent from each other and each represents a hydrogen atom, a C₁₋₈alkyl group or a C₃₋₈ cycloalkyl group, or together with the nitrogenatom to which they bind, represents a C₂₋₅ saturated cyclic amino groupwhich may, in addition to the nitrogen atom, contain an oxygen atom, asulfur atom or a nitrogen atom, and may be further substituted with aC₁₋₄ alkyl group which may be substituted with a halogen atom;

R² represents (1) a hydrogen atom, (2) a halogen atom, (3) a grouprepresented by the formula —NR⁶R⁷ (wherein R⁶ and R⁷ are the same as ordifferent from each other and each represents a hydrogen atom, a C₂₋₅acyl group, a C₁₋₈ alkyl group or a C₃₋₈ cycloalkyl group, or R⁶ and R⁷together with the nitrogen atom to which they bind form a C₂₋₅ saturatedcyclic amino group which may, in addition to the nitrogen atom, containan oxygen atom, a sulfur atom or a nitrogen atom, and may be furthersubstituted with a C₁₋₄ alkyl group which may be substituted with ahalogen atom, (4) a C₂₋₈ alkynyl group which may be substituted with ahalogen atom, a hydroxyl group, a C₁₋₄ alkyl group or a C₃₋₆ cyloalkylgroup, (5) a C₃₋₈ alkenyl group which may be substituted with a halogenatom, a hydroxyl group or a C₁₋₄ alkyl group, (6) a C₁₋₈ alkyl groupwhich may be substituted with a halogen atom, a hydroxyl group or a C₁₋₄alkyl group or (7) a C₁₋₈ alkoxy group which may be substituted with ahalogen atom, a hydroxyl group or a C₁₋₄ alkyl group;

R³ represents (1) a C₃₋₈ alkynyl group which may be substituted with ahalogen atom, a hydroxyl group or a C₁₋₄ alkyl group, (2) a C₃₋₈ alkenylgroup which may be substituted with a halogen atom, a hydroxyl group ora C₁₋₄ alkyl group, (3) a C₁₋₈ alkyl group which may be substituted witha halogen atom, a hydroxyl group or a C₁₋₄alkyl group, (4) an aryl groupwhich may have a substituent group, (5) a heteroaryl group which mayhave a substituent group, (6) an 1,2-dihydro-2-oxopyridyl group whichmay be substituted with (a) a halogen atom or a C₁₋₆ alkyl group, andwhose nitrogen atom may be substituted with (b-1) a C₁₋₆ alkyl groupwhich may be substituted with a halogen atom, a hydroxyl group or acarboxyl group which may have a protective group, (b-2) a C₃₋₆cycloalkyl-C₁₋₄ alkyl group which may have a substituent group or (b-3)a C₃₋₆ cycloalkyl group which may have a substituent group, (7) adihydrooxopyrimidyl group which may be substituted with (a) a halogenatom or a C₁₋₆ alkyl group, and whose nitrogen atom is substituted with(b-1) a C₁₋₆ alkyl group which may be substituted with a halogen atom, ahydroxyl group or a carboxyl group which may have a protective group,(b-2) a C₃₋₆ cycloalkyl-C₁₋₄ alkyl group which may have a substituentgroup or (b-3) a C₃₋₆ cycloalkyl group, or (8) a dihydrooxo- ortetrahydrodioxopyrazinyl group which may be substituted with (a) ahalogen atom or a C₁₋₆ alkyl group, and whose nitrogen atom issubstituted with (b-1) a C₁₋₆ alkyl group which may be substituted witha halogen atom, a hydroxyl group or a carboxyl group which may have aprotective group, (b-2) a C₃₋₆ cycloalkyl-C₁₋₄ alkyl group which mayhave a substituent group or (b-3) a C₃₋₆ cycloalkyl group;

Ar represents (1) an aryl group which may have a substituent group, (2)a heteroaryl group which may have a substituent group, (3) an oxopyridylgroup which may be substituted with a halogen atom or a C₁₋₆ alkyl groupand whose nitrogen atom is substituted with a C₁₋₆ alkyl group or a C₃₋₆cycloalkyl group, or (4) an oxopyrimidyl group which may be substitutedwith a halogen atom or a C₁₋₆ alkyl group and whose nitrogen atom issubstituted with a C₁₋₆ alkyl group or a C₃₋₆ cycloalkyl group; and

Q and W are the same as or different from each other and each representsN or CH,

provided that, in the above, when R² is 1) a C₂₋₈ alkynyl group whichmay be substituted with a halogen atom, a hydroxyl group, a C₁₋₄ alkylgroup or a C₃₋₆ cycloalkyl group; 2) a C₃₋₈ alkenyl group which may besubstituted with a halogen atom, a hydroxyl group or a C₁₋₄ alkyl groupor 3) a C₁₋₈ alkyl group which may be substituted with a halogen atom, ahydroxyl group or a C₁₋₄ alkyl group, R³ is not 1) a C₁₋₈ alkyl groupwhich may be substituted with a halogen atom, a hydroxyl group or a C₁₋₄alkyl group, or is not 2) an aryl group which may have a substituentgroup), a pharmaceutically acceptable salt thereof or a hydrate of them(WO 2001/2400).

(11) Pyrrolo[2,3d]pyrimidine derivatives represented by the formula:

wherein R₁ and R₂ independently represent a hydrogen atom, an alkylgroup which may have a substituent group, an aryl group which may have asubstituent group, an alkyl aryl group which may have a substituentgroup or a hetero ring which may have a substituent formed by eachother;

R₃ represents a hydrogen atom, an alkyl group which may have asubstituent group, an aryl group which may have a substituent group oran alkyl aryl group which may have a substituent group;

R₄ represents a hydrogen atom, an alkyl group which may have asubstituent group, an aryl group which may have a substituent group oran alkyl aryl group which may have a substituent group; and

R₅ and R₆ independently represent a hydrogen atom, an alkyl group whichmay have a substituent group, an aryl group which may have a substituentgroup or an alkyl aryl group which may have a substituent group, or R₄and R5, or R5 and R₆ may be combined with each other to form aheteroring or hydrocarbon ring which may have a substituent group(WO9962518).

(12) 8-Phenyl or 8-cycloalkylxanthine, and xanthine derivatives having asubstituent group at the 8-position, which are represented by theformula:

wherein 1) R₁ represents a hydrogen, an alkyl group, a cycloalkyl groupor an aryl group; R₂ represents a cycloalkyl group or an aryl group; andR₃ represents a phenyl group, a cycloalkyl group, a phenyl group havinga substituent group or a cycloalkyl group having a substituent group, or2) R₁ and R₂ each represents a group shown by the formula:

and R₃ represents a group shown by the formula:

(WO9942093).

(13) 1) 3-n-Propylxanthine; 2) 1,3-dipropyl-8-(p-acrylic)phenylxanthine;3) 1,3-dipropyl-8-cyclopentylxanthine; 4)1,3-dipropyl-8-(p-sulfophenyl)xanthine; 5) xanthinamine analogues; 6)1,3-dipropyl-8-[2-(5,6-epoxynorbonyl)]xanthine; and 7)1,3-dimethylcyclohexyl-8-phenyl(4-acrylate)xanthine (U.S. Pat. No.6,060,481).

(14) Substituted8-phenylxanthine derivative I represented by theformula:

(wherein R and R¹ independently represent hydrogen, (C₁ to C₈) alkyl,(C₂ to C₈) alkenyl, (C₂ to C₈) alkynyl, (C₁ to C₈) alkoxy, (C₃ to C₈)cycloalkyl, (C₄ to C₁₆) cycloalkyl alkyl, a heteroring, (C₆ to C₁₀)aryl, (C₇ to C₁₈) aralkyl or heteroaryl;

Z means a group represented by:

X represents (C₁ to C₈) alkylene, (C₂ to C₈) alkenylene and (C₂ to C₈)alkynylene, and one carbon atom of the alkylene, alkenylene oralkynylene may be substituted with a substituent group containing —O—,—N(R⁴)C(O)—, —OC(O)—, —N(R⁵) (R⁶)—, —S—, —S(O)— or —SO₂—;

R² represents hydrogen, (C₁ to C₈) alkyl, (C₂ to C₈) alkenyl, (C₂ to C₈)alkynyl, (C₁ to C₈) alkoxy, (C₃ to C₈) cycloalkyl, (C₄ to C₁₆)cycloalkyl alkyl, (C₆ to C₁₀) aryl, (C₇ to C₁₈) aralkyl, a heteroring orheteroaryl, and R² may be substituted with one or more substituentgroups selected from the group consisting of substituent groupscontaining —OH, —SH, —NH₂, —NHR⁷, —CN, —COOH and —SO₃H;

R⁴, R⁵, R⁶ and R⁷ independently represent hydrogen, (C₁ to C₈) alkyl,(C₂ to C₈) alkenyl, (C₃ to C₈) cycloalkyl, (C₆ to C₁₀) aryl, (C₇ to C₁₈)aralkyl or hetero-(C₁ to C₆) alkyl;

R⁸ represents hydrogen, (C₃ to C₈) cycloalkyl, (C₄ to C₁₆) cycloalkylalkyl, (C₇ to C₁₈) aralkyl, a heteroring or heteroaryl, each of whichmay be substituted with one or more substituent groups which areindependently selected from oxo, (C₁ to C₈) alkyl, halo (C₁ to C₆)alkyl, (C₂ to C₈) alkenyl, (C₆ to C₁₀) aryl, (C₇ to C₁₈) aralkyl,heteroaryl, halo, —OR¹⁵, —CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶, —C(O)R¹⁶,—NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ or —SO₃H, or R⁸represents (C₁ to C₈) alkyl which is substituted with one or moresubstituent groups which are selected independently from oxo, (C₂ to C₈)alkenyl, (C₆ to C₁₀) aryl, (C₇ to C₁₈) aralkyl, heteroaryl,—OR¹⁵, halo,—CN, —NO₂, —OC(O)R¹⁶, —C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸,—SR¹⁹, —SO₂R²⁰ or —SO₃H, or R⁸ represents (C₆ to C₁₀) aryl which issubstituted with one or more substituent groups which are selectedindependently from (C₁ to C₈) alkyl, halo (C₁ to C₆) alkyl, (C₂ to C₈)alkenyl, (C₇ to C₁₈) aralkyl, heteroaryl, —OR¹⁵, —CN, —NO₂, —CO₂R¹⁵,—OC(O)R¹⁶, —C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹,—SO₂R²⁰ or —SO₃H;

R⁹ represents —NR¹⁰R¹¹, or (C₃ to C₈) cycloalkyl, (C₄ to C₁₆)cycloalkylalkyl, (C₇ to C₁₈) aralkyl, a heteroring or heteroaryl, whichmay be substituted with one or more substituent groups selectedindependently from oxo, (C₁ to C₈) alkyl, halo (C₁ to C₆) alkyl, (C₂ toC₈) alkenyl, (C₆ to C₁₀) aryl, (C₇ to C₁₈) aralkyl, heteroaryl, —OR¹⁵,halo, —CN, —NO₂, —CO₂R⁵, —OC(O)R¹⁶, —C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴,—C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ or —SO₃H, or R⁹ represents (C₁ to C₈) alkylwhich is substituted with one or more substituent groups which areselected independently from oxo, (C₂ to C₈) alkenyl, (C₆ to C₁₀) aryl,(C₇ to C₁₈) aralkyl, heteroaryl, —OR¹⁵, halo, —CN, —NO₂, —OC(O)R¹⁶,—C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ or—SO₃H, or R⁹ represents (C₆ to C₁₀) aryl which is substituted with oneor more substituent groups which are selected independently from (C₁ toC₈) alkyl, halo (C₁ to C₆) alkyl, (C₂ to C₈) alkenyl, (C₇ to C₁₈)aralkyl, heteroaryl, —OR¹⁵, —CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶, —C(O)R¹⁶,—NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ or —SO₃H;

R¹⁰ and R¹¹ independently represent halogen, (C₁ to C₈) alkyl, (C₂ toC₈) alkenyl, (C₃ to C₈) cycloalkyl, (C₆ to C₁₀) aryl, (C₇ to C₁₈)aralkyl, a heteroring, heteroaryl, —C(O)(CH₂)_(n)CO₂R₁₂, —C(O)R²¹═CR²²(CH₂)_(m)CO₂R¹², —C(O)R¹², —C(O) (C₃ to C₈) cycloalkyl or —C(O) (C₃ toC₈) cycloalkenyl, each of which may be substituted with one or moresubstituent groups which are independently selected from oxo, (C₁ to C₈)alkyl, halo(C₁ to C₆) alkyl, (C₂ to C₈) alkenyl, (C₆to C₁₀) aryl, (C₇ toC₁₈) aralkyl, heteroaryl, —OR¹⁵, halo, —CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶,—C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ or—SO₃H, or R¹⁰ and R¹¹ together with a nitrogen atom may form aheteroring or heteroaryl ring, each of which may be substituted with oneor more substituent groups which are independently oxo, (C₁ to C₈)alkyl, halo (C₁ to C₆) alkyl, (C₂ to C₈) alkenyl, (C₆ to C₁₀) aryl, (C₇to C₁₈) aralkyl, heteroaryl, —OR¹⁵, halo, —CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶,—C(O)R¹⁶, —NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ or—SO₃H; n is 1 to 6; m is 0 to 4;

R¹²represents hydrogen, (C₁ to C₈) alkyl, (C₂ to C₈) alkenyl, (C₂ to C₈)alkynyl, (C₃ to C₈) cycloalkyl, (C₄ to C₁₆) cycloalkyl alkyl, (C₆ toC₁₀) aryl, (C₇ to C₁₈) aralkyl, a heteroring or heteroaryl;

R¹² may be substituted with one or more substituent groups which areindependently selected from oxo, (C₁ to C₈) alkyl, halo (C₁ to C₆)alkyl, (C₂ to C₈) alkenyl, (C₆ to C₁₀) aryl, (C₇ to C₁₈) aralkyl,heteroaryl, —OR¹⁵, halo, —CN, —NO₂, —CO₂R¹⁵, —OC(O)R¹⁶, —C(O)R¹⁶,—NR¹³R¹⁴, —N(R²³)C(O)R²⁴, —C(O)NR¹⁷R¹⁸, —SR¹⁹, —SO₂R²⁰ or —SO₃H;

R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²³ and R²⁴ independentlyrepresent hydrogen, (C₁ to C₈) alkyl, (C₂ to C₈) alkenyl, (C₃ to C₈)cycloalkyl, (C₆ to C₁₀) aryl, (C₇ to C₁₈) aralkyl or halo (C₁ to C₆)alkyl; and

R²¹ and R²² independently represent hydrogen, (C₁ to C₈) alkyl, (C₂ toC₈) alkenyl, (C₃ to C₈) cycloalkyl, (C₆ to C₁₀) aryl or (C₇ to C₁₈)aralkyl,

provided that when —NR⁸R⁹ is not aminoalkyl, aminodialkyl or hydradino,or both R and R⁸ are hydrogen and both R¹ and R² are alkyl, R⁹ is not2-hydroxyethyl, 2-thiolethyl, 2-haloethyl, 2,2-dimethoxyethyl,2-acetoxyethyl, 1-methyl-2-phenylethyl, 4-methylphenyl or4-hydroxyphenyl) or a pharmacologically acceptable salt thereof (WO0073307).

(15) Aryl pyridinylthiazole derivatives represented by the formula:

(wherein Ar represents an unsubstituted or substituted aryl group whichbound via a carbon atom of the aromatic ring thereof to a carbon atom ofthe thiazole shown in the formula; and R represents a hydrogen, an acylgroup or an aromatic ring containing 10 or more carbon atoms which boundvia a carbon atom of the aromatic ring thereof to the nitrogen atomshown in the formula, and when Ar is phenyl or 4-methoxyphenyl, R is nothydrogen) or a salt thereof (WO9964418).

(16) 1) 3-n-Propylxanthine; 2) 1,3-dipropyl-8-(p-acrylic)phenylxanthine;3) 1,3-dipropyl-8-cyclopentylxanthine; 4)1,3-dipropyl-8-(p-sulfophenyl)xanthine; 5) a xanthineamine congener; and6) 1,3-dipropyl-8-[2-(5,6-epoxynorbonyl)]xanthine (U.S. Pat. No.6,060,481).

(17) Compounds represented by the formulae:

R X ZM241385 4-HO-Ph(CH₂)₂NH N LUF5441 4-HO-Ph(CH₂)₂NH CH LUF5443 MeS NLUF5452 Ph(CH₂)₂NH N LUF5451 Bn-NH N LUF5453 Ph-NH N LUF5478 Ph(CH₂)₃NHN LUF5455 4-Cl—Bn-NH N LUF5456 3-Cl—Bn-NH N LUF5457 3,4-di-Cl—Bn-NH NLUF5458 4-MeO-Bn-NH N LUF5459 4-Me-Bn-NH N LUF5460 (R)-α-Me-Bn-NH NLUF5461 (S)-α-Me-Bn-NH N LUF5479 (Ph)₂CHNH N LUF5462 (Bn)(CH₃)N NLUF5475 PhNHNH N LUF5477 Cyclohexyl-CH₂NH N

XAC

CGS15943(Drug Development Research 48: 95-103 (1999)).

(18) Compounds represented by the formulae:

(Drug Development Research 47: 45-53 (1999)).

(19) Compounds represented by the formula:

(Journal of Medicinal Chemistry, 41, 2835-2845 (1998)).

(20) Compounds represented by the formula:

TABLE 7 R₁ X R₂ n-Pr OCH₂ OH n-Pr OCH₂ O-succinimide n-Pr OCH₂NHN-dimethylmaleyl n-Pr OCH₂ NH(CH₂)₂NH₂ allyl OCH₂ OH n-butyl OCH₂ OHBn OCH₂ OH n-Pr CH═CH OH c-HexMe CH═CH OH Bn CH═CH OH n-Pr OCH₂ NH₂ n-PrOCH₂ NH—Ph n-Pr OCH₂ NH—CH₂Ph n-Pr OCH₂ NH—CH(Ph)₂ n-Pr OCH₂ N(CH₂Ph)₂n-Pr OCH₂ N(CH₃)Ph n-Pr OCH₂ N(CH₂COOEt)₂ n-Pr OCH₂ NH—Ph(2-COCH₃) n-PrOCH₂ NH—Ph(3-COCH₃) n-Pr OCH₂ NH—Ph(4-COCH₃) n-Pr OCH₂ NH—Ph(4-COOCH₃)n-Pr OCH₂ NH—Ph(4-CONH₂) n-Pr OCH₂ NH—Ph(4-CONHCH₃) n-Pr OCH₂NH—Ph(4-COOH) n-Pr OCH₂ NH—Ph(4-CH₃) n-Pr OCH₂ NH—Ph(4-OH) n-Pr OCH₂NH—Ph(4-CN) n-Pr OCH₂ NH—Ph(4-NO₂) n-Pr OCH₂ NH—Ph(4-CF₃) n-Pr OCH₂NH—Ph(4-F) n-Pr OCH₂ NH—Ph(4-Cl) n-Pr OCH₂ NH—Ph(4-Br) n-Pr OCH₂NH—Ph(4-I) n-Pr CH═CH NHN-dimethylmaleyl n-Pr CH═CH NH—Ph(2-COCH₃) EtOCH₂ NH—Ph(4-CH₃) Et OCH₂ NH—Ph(4-CH₂CONH(CH₂)₂NH₂)(Journal of Medicinal Chemistry, 43, 1165-1172 (2000)).

(21) Compounds represented by the formula:

X Y Z H NH₂ Br H NH₂ O—(CH₂)₂—C₆H₅ H NH₂ C≡C—(CH₂)₃—CH₃ O—(CH₂)₂—C₆H₅NH₂ H NH—(CH₂)₂—C₆H₅ NH₂ H C≡C—(CH₂)₃—CH₃ NH₂ H H NH—(CH₂)₂—C₆H₅ H HC≡C—(CH₂)₂—C₆H₅ H H NH—(CH₂)₂—C₆H₅ Br(Bioorganic & Medicinal Chemistry, 6, 523-533 (1998)).

(22) Compounds represented by the formulae:

(Naunyn-Schmiedeberg's Arch Pharmacol 362: 382-391 (2000)).

(23) 1) 8-Cyclohexyl-1,3-dipropyl-7-methylxanthine; 2)3,7-dimethyl-1-propargylxanthine; 3) 7-(2-chloroethyl)-theophylline; 4)3-isobutyl-7-methylxanthine; 5) 1,7-dimethylxanthine (BiochemicalPharmacology, 47(5), 801-814, 1994).

(24) 1) 8-FB—PTP

(5-amino-8-(4-fluorobenzyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine);2) 3-propylxanthine (British Journal of Pharmacology 119, 1286-1290(1996)).

(25) Compounds represented by the formula:

Ar R² C₆H₅ c-C₆H₁₀(OH) 2-furyl c-C₆H₁₀(OH) 2-thienyl c-C₆H₁₀(OH)2-pyridyl c-C₆H₁₀(OH) 2-FC₆H₄ c-C₆H₁₀(OH) 3-FC₆H₄ c-C₆H₁₀(OH) 4-FC₆H₄c-C₆H₁₀(OH) 3-ClC₆H₄ c-C₆H₁₀(OH) 4-ClC₆H₄ c-C₆H₁₀(OH) 3-(CN)C₆H₄c-C₆H₁₀(OH) 3-MeC₆H₄ c-C₆H₁₀(OH) 3-MeOC₆H₄ c-C₆H₁₀(OH) 3-FC₆H₄c-C₅H₈(OH) 3-FC₆H₄ c-C₇H₁₂(OH) 3-FC₆H₄ (CH₃)₂(OH)C 3-FC₆H₄ (C₂H₅)₂(OH)C3-FC₆H₄ c-C₅H₉ H c-C₆H₁₀(OH)(Journal of Medicinal Chemistry 44, 170-179 (2001)).

(26) 1) 1-Methylxanthine; 2) 3-methylxanthine; 3) 7-methylxanthine; 4)3-isobutyl-1-methylxanthine; 5) 1,3-dimethyl-8-cyclopentylxanthine(Pharmaceutica Acta Helvetiae 68, 77-111 (1993)).

(27) Compounds represented by the formula:

wherein R represents an aliphatic or alicyclic amino group (for examplea C₁ to C₆ alkylamino group, a C₁ to C₆ dialkylamino group, a piperidinogroup, a piperazino group, a pyrrolidino group, apyrrolino group, amorpholino, or an aminocyclohexyl derivative (WO 01/16134).

For example, the defecation-promoting actions of 8-phenyltheophylline(“8-PT” in the table below) and5-[6-amino-8-(3-fluorophenyl)-9H-9-purinyl]-1-methyl-1,2-dihydro-2-pyridinone (Compound II in the table below) disclosed in ExampleNumber 5 described in WO2001/2400 were as shown below. 8-PT can beeasily produced according to the description of Drug DevelopmentResearch 47: 45-53 (1999), or is easily available as a commercialproduct (in this test, it was purchased from Sigma). TABLE 8 The numberof Compound Dose fecal pellets/3 rats Control —  3.25 ± 2.02 8-PT 3mg/kg  8.75 ± 1.75 NS 10 mg/kg  13.75 ± 0.85 ** Compound I 3 mg/kg 20.75± 3.15 *** Control —  2.5 ± 0.87 Compound II 1 mg/kg  12.5 ± 1.44 ** 3mg/kg  18.5 ± 1.94 *** 10 mg/kg  20.75 ± 1.70 *** Compound I 3 mg/kg19.75 ± 2.50 ***The number of cages; n = 4 cages/group (12 rats/group)** p < 0.01,*** p < 0.001,NS; not significant, Dunnett's test** p < 0.01,*** p < 0.001, Dunnett's test

The present invention also relates to a compound represented by theabove formula (I) or (II) or a salt of them. The compound is a novelpyrimidine compound found in the process of searching for thedefecation-promoting pharmaceutical composition according to the presentinvention. The compound is a compound exhibiting an excellentantagonistic action on adenosine A₂ receptor, particularly on adenosineA_(2b) receptor and having an excellent defecation-promoting action.

The structural formulae of the compounds represented by the formula (I)or (II) in the present invention or a salt thereof may, for convenience'sake, indicate a certain isomer, but this invention encompasses allpossible isomers which can occur in the structures of the compounds, forexample geometric isomer, optical isomer based on asymmetrical carbon,stereoisomer and tautomer, as well as a mixture of such isomers, so thecompound of the invention may be any isomers or a mixture thereofwithout limitation to the formulae shown for convenience' sake. Compound(I) or (II) can have an intramolecular asymmetrical carbon to occur asoptically active isomers or racemic modifications, and any of suchcompounds are included in this invention without limitation. When thereis crystal polymorphism, the compound of the invention may be in asingle crystal form or a mixed crystal form without limitation. Compound(I) or (II) in the invention or salts thereof may be anhydrides orhydrates, any of which fall under the claims in this specification.Further, metabolites formed by decomposition of Compound (I) or (II) inthe living body, as well as prodrugs of Compound (I) or (II) or saltsthereof, also fall under the claims in this specification.

The “halogen atom” used in this specification refers to an atom such as,for example, a fluorine atom, a chlorine atom, a bromine atom or aniodine atom, preferably a fluorine atom, a chlorine atom or a bromineatom, more preferably a fluorine atom or a chlorine atom, still morepreferably a fluorine atom.

The “C₁₆ alkyl group” used in this specification refers to an alkylgroup containing 1 to 6 carbon groups, and examples thereof includelinear or branched alkyl groups, preferably a methyl group, ethyl group,n-propyl group, iso-propyl group, n-butyl group, iso-butyl group,sec-butyl group, tert-butyl group, n-pentyl group, 1,1-dimethylpropylgroup, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropylgroup, 2-ethylpropyl group, n-hexyl group, 1-methyl-2-ethylpropyl group,1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group,1-propylpropyl group, 1-methylbutyl group, 2-methylbutyl group,1,1,-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutylgroup, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutylgroup, 2-methylpentyl group, 3-methylpentyl group etc., more preferablya methyl group, ethyl group, n-propyl group, iso-propyl group, n-butylgroup, iso-butyl group, sec-butyl group, tert-butyl group, n-pentylgroup etc.

The “C₁₋₆ alkoxy group” used in this specification refers to an alkoxygroup containing 1 to 6 carbon groups, and preferable examples includee.g. a methoxy group, ethoxy group, n-propoxy group, iso-propoxy group,sec-propoxy group, n-butoxy group, iso-butoxy group, sec-butoxy group,tert-butoxy group, n-pentyloxy group, iso-pentyloxy group, sec-pentyloxygroup, n-hexoxy group, iso-hexoxy group, 1,1-dimethylpropyloxy group,1,2-dimethylpropoxy group, 2,2-dimethylpropyloxy group, 2-ethylpropoxygroup, 1-methyl-2-ethylpropoxy group, 1-ethyl-2-methylpropoxy group,1,1,2-trimethylpropoxy group, 1,1,2-trimethyl propoxy group,1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 2,2-dimethylbutoxygroup, 2,3-dimethylbutyloxy group, 1,3-dimethylbutyloxy group,2-ethylbutoxy group, 1,3-dimethylbutoxy group, 2-methylpentoxy group,3-methylpentoxy group, hexyloxy group etc.

The “C₁₋₆ alkoxy-carbonyl group” used in this specification refers to acarbonyl group to which a C₁₋₆ alkoxy group was bound, and examplesthereof include a methoxycarbonyl group, ethoxycarbonyl group,n-propoxycarbonyl group, iso-propoxycarbonyl group, sec-propoxycarbonylgroup, n-butoxycarbonyl group, iso-butoxycarbonyl group,sec-butoxycarbonyl group, tert-butoxycarbonyl group, n-pentyloxycarbonylgroup, iso-pentyloxycarbonyl group, sec-pentyloxycarbonyl group,n-hexoxycarbonyl group, iso-hexoxycarbonyl group,1,1-dimethylpropyloxycarbonyl group, 1,2-dimethylpropoxycarbonyl group,2,2-dimethylpropoxycarbonyl group, 2-ethylpropoxycarbonyl group,1-methyl-2-ethylpropoxycarbonyl group, 1-ethyl-2-methylpropoxycarbonylgroup, 1,1,2-trimethylpropoxycarbonyl group,1,1,2-trimethylpropoxycarbonyl group, 1,1-dimethylbutoxycarbonyl group,1,2-dimethylbutoxycarbonyl group, 2,2-dimethylbutoxycarbonyl group,2,3-dimethylbutyloxycarbonyl group, 1,3-dimethylbutyloxycarbonyl group,2-ethylbutoxycarbonyl group, 1,3-dimethylbutoxycarbonyl group,2-methylpentoxycarbonyl group, 3-methylpentoxycarbonyl group,hexyloxycarbonyl group etc.

The “acyl group” used in this specification refers to an atomic groupderived from a C₁₋₇ fatty acid carboxyl group by removing its OH group,and preferable groups include e.g. an acetyl group, propionyl group,butyroyl group etc.

The “C₁₋₆ alkyl sulfonyl group” used in this specification refers to asulfonyl group to which a C₁₋₆ alkyl group was bound, and preferablegroups include a methylsulfonyl group, ethylsulfonyl group,n-propylsulfonyl group, iso-propylsulfonyl group, n-butylsulfonyl group,iso-butylsulfonyl group, sec-butylsulfonyl group, tert-butylsulfonylgroup, n-pentylsulfonyl group, n-hexylsulfonyl group etc.

In the formula (I) or (II), A represents a phenyl group, a pyridylgroup, a thienyl group or a furyl group which may be substituted withone or two groups selected from a halogen atom, a hydroxyl group, a C₁₋₆alkyl group, a C₁₋₆ alkoxy group and a C₁₋₆ alkoxy-carbonyl group, andpreferable examples of the group A are not particularly limited. Morepreferable examples of the group A include a phenyl group, a pyridylgroup, a thienyl group and a furyl group, each of which may besubstituted with one to three groups selected from a fluorine atom, achlorine atom, a hydroxyl group, a methyl group, an ethyl group, amethoxy group and an ethoxy group. Still more preferable groupsinclude 1) a phenyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridylgroup, 2-furyl group, 3-furyl group, 2-thienyl group and 3-thienylgroup, each of which is unsubstituted, and 2) a phenyl group, 2-pyridylgroup, 3-pyridyl group, 4-pyridyl group, 2-furyl group, 3-furyl group,2-thienyl group, 3-thienyl group etc., each of which is substituted withone to three groups selected from a fluorine atom, chlorine atom,hydroxyl group, methyl group, ethyl group, methoxy group and ethoxygroup.

In the formula (I), B represents a pyridyl group which may besubstituted with one or more groups selected from a halogen atom, ahydroxyl group, a C₁₋₆ alkyl group and an amino group, and preferableexamples of the group B are not particularly limited. More preferableexamples of the group B is 1) an unsubstituted 4-pyridyl group or 2) a4-pyridyl group which is substituted with one to three groups selectedfrom a fluorine atom, a chlorine atom, a hydroxyl group, a methyl group,an ethyl group, a n-propyl group, an iso-propyl group and an aminogroup.

In the formula (II), B′ represents a 1,2-dihydro-2-pyridinone-4-yl groupwhich may be substituted with one or more groups selected from a halogenatom, a hydroxyl group, a C₁₋₆ alkyl group and an amino group, andpreferable examples of the group B′ are not particularly limited, andmore preferable examples include 1) an unsubstituted1,2-dihydro-2-pyridinone-4-yl group, 2) an 1,2-dihydro-2-pyridinone-4-ylgroup which is substituted with one to two groups selected from afluorine atom, chlorine atom, hydroxyl group, methyl group, ethyl group,n-propyl group, iso-propyl group and amino group, and a still furtherpreferable group is an unsubstituted 1,2-dihydro-2-pyridinone-4-ylgroup.

In the above formula (I) or (II), R¹ represents a hydrogen atom, amorpholinyl group, or a group represented by the formula —NR^(1a)R^(1b)(wherein R^(1a) and R^(1b) are the same as or different from each otherand each represents a hydrogen atom, a C₁₋₆ alkyl group, a C₁₋₆ acylgroup, a phenyl group or a C₁₋₆ alkyl sulfonyl group), and 1) a hydrogenatom, 2) a 4-morpholinyl group, 3) an amino group, 4) a C₁₋₆ alkylaminogroup (for example, a methylamino group, ethylamino group, n-propylaminogroup, iso-propylamino group etc.), 5) an N,N-diC₁₋₆ alkyl amino group(for example, a dimethylamino group, diethylamino group, etc.), 6) aC₁₋₆acyl amino group (for example, an acetamide group, propionylaminogroup, etc.), 7) an N,N-C₁₋₆ alkyl (C₁₋₆ acyl) amino group and 8) a C₁₋₆alkylsulfonylamino group (for example, a methylsulfonylamino group, anethylsulfonylamino group, a n-propylsulfonylamino group,aniso-propylsulfonylamino group, etc.) are more preferable.

In the formula (I) or (II), R² represents a hydrogen atom or a grouprepresented by the formula —NR^(2a)R^(2b) (wherein R^(2a) and R^(2b) arethe same as or different from each other and each represents a hydrogenatom or a C₁₋₆ alkyl group, and more preferable groups include ahydrogen atom, an amino group, a methyl amino group, an ethyl aminogroup, an N,N-dimethylamino group, an N,N-methylethylamino group, etc.

Preferable examples of Compound (I) or (II) include the followingcompounds:

6-(3-flurophenyl)-5-(4-pyridyl)-2,4-pyrimidinediamine;

-   6-(2-furyl)-5-(4-pyridyl)-2,4-pyrimidinediamine;-   4-(2-furyl)-5-(4-pyridyl)-2-pyrimidinylamine;-   4-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinylamine;-   4-phenyl-5-(4-pyridyl)-2-pyrimidinylamine;-   5-(4-pyridyl)-4-(2-thienyl)-2-pyrimidinylamine;-   4-(2-pyridyl)-5-(4-pyridyl)-2-pyrimidinylamine;-   4-(3-fluorophenyl)-5-(4-pyridyl)pyrimidine;-   4-(3-fluorophenyl)-5-(2-fluoro-4-pyridyl)pyrimidine;-   4-(3-fluorophenyl)-5-(2-fluoro-4-pyridyl)-2-pyrimidinylamine;-   N-[4-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinyl]-N,N-dimethylamine;-   N-[4-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinyl]-N-methylamine;-   4-[4-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinyl]morpholine;-   N-[4-(3-fluorophenyl)-5-(2-fluoro-4-pyridyl)-2-pyrimidinyl]-N-methylamine;    4-[4-(3-fluorophenyl)-2-(methylamino)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone;-   N-ethyl-N-[4-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinyl]amine;-   N1-[4-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinyl]acetamide;-   N1-[4-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinyl]-N1-methylacetamide;-   N1-[4-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinyl]propanamide;-   N1-[4-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinyl]butanamide;-   N1-[4-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinyl]-N1-methylpropanamide;-   4-(3-fluorophenyl)-5-(2-methyl-4-pyridyl)-2-pyrimidinylamine;-   N1-ethyl-N1-[4-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinyl]propanamide;-   N1-[4-(3-fluorophenyl)-5-(2-fluoro-4-pyridyl)-2-pyrimidinyl]propanamide;-   N1-[4-(3-fluorophenyl)-5-(2-methyl-4-pyridyl)-2-pyrimidinyl]propanamide;-   4-[2-amino-4-(3-fluorophenyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone;-   N-ethyl-N-[4-(3-fluorophenyl)-5-(2-fluoro-4-pyridyl)-2-pyrimidinyl]amine;-   4-[2-(ethylamino)-4-(3-fluorophenyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone;-   N-[4-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinyl]-N-propylamine;-   N-[4-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinyl]-N-phenylamine;-   N-ethyl-N-[4-(3-fluorophenyl)-5-(2-methyl-4-pyridyl)-2-pyrimidinyl]amine;-   5-(2,6-dimethyl-4-pyridyl)-4-(3-fluorophenyl)-2-pyrimidinylamine;-   N-[5-(2,6-dimethyl-4-pyridyl)-4-(3-fluorophenyl)-2-pyrimidinyl]-N-ethylamine;-   4-(3-fluorophenyl)-5-(3-methyl-4-pyridyl)-2-pyrimidinylamine;-   5-(3-ethyl-4-pyridyl)-4-(3-fluorophenyl)-2-pyrimidinylamine;-   5-(2-amino-4-pyridyl)-4-(3-fluorophenyl)-2-pyrimidinylamine;-   N4-methyl-6-(3-fluorophenyl)-5-(4-pyridyl)-2,4-pyrimidinediamine;-   N4,N4-dimethyl-6-(3-fluorophenyl)-5-(4-pyridyl)-2,4-pyrimidinediamine;-   N-ethyl-N-[4-(2-furyl)-5-(4-pyridyl)-2-pyrimidinyllamine;-   N-ethyl-N-[4-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinyl]amine;-   N-ethyl-N-[4-phenyl-5-(4-pyridyl)-2-pyrimidinyl]amine;-   N-ethyl-N-[5-(4-pyridyl)-4-(2-thienyl)-2-pyrimidinyl]amine;-   5-(3-ethyl-4-pyridyl)-4-(2-furyl)-2-pyrimidinyl amine;-   N-ethyl-N-[5-(3-ethyl-4-pyridyl)-4-(2-furyl)-2-pyrimidinyl]amine;-   4-(2,5-dimethyl-3-furyl)-5-(3-ethyl-4-pyridyl)-2-pyrimidinylamine;-   N-[4-(2,5-dimethyl-3-furyl)-5-(3-ethyl-4-pyridyl)-2-pyrimidinyl]-N-ethylamine;-   5-(2,6-dimethyl-4-pyridyl)-6-(3-fluorophenyl)-2,4-pyrimidinediamine;-   4-(3-methyl-2-furyl)-5-(4-pyridyl)-2-pyrimidinylamine;-   N-[4-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinyl]methanesulfonamide;    4,5-di(4-pyridyl)-2-pyrimidinylamine;-   4-(4-methoxyphenyl)-5-(4-pyridyl)-2-pyrimidinylamine;-   4-(3,4-dimethoxyphenyl)-5-(4-pyridyl)-2-pyrimidinylamine;-   4-[2-amino-5-(4-pyridyl)-4-pyrimidinyl]phenol; methyl-   3-[2-amino-5-(4-pyridyl)-4-pyrimidinyl]benzoate; and-   N4,N4-dimethyl-6-(2-furyl)-5-(4-pyridyl)-2,4-pyrimidinediamine.

The compounds represented by the above formula (I) or (II) in thisinvention can be produced by various methods, but typical productionmethods are as follows. In the following production methods, “roomtemperature” refers usually to 10 to 35° C.

wherein A represents a phenyl group, pyridyl group, thienyl group orfuryl group which may be substituted with one or two groups selectedfrom a halogen atom, a hydroxyl group, a C₁₋₆alkyl group, a C₁₋₆ alkoxygroup and a C₁₋₆ alkoxy-carbonyl group, B represents a pyridyl groupwhich may be substituted with one or more groups selected from a halogenatom, a hydroxyl group, a C₁₋₆ alkyl group and an amino group, and Xrepresents a C₁₋₈ alkyl group. Step A₁ is a step of producing1,2-biaryl-1-ethanone compound (3) which is an intermediate forproduction of the compound represented by the above formula (I) in thisinvention. That is, Compound (3) is obtained through condensation viaalcohol elimination by reacting an aromatic carboxylate (1) with4-methylpyridine derivative (2) in a solvent in the presence of a base.The base used is varied depending on the starting materials, reagents,solvent etc. used, and is not particularly limited insofar as thereaction is not inhibited, and preferable examples of the base includesecondary amine metal salts such as lithium bis(trimethylsilyl)amide andlithium diisopropylamide. The solvent used is varied depending on thestarting materials and reagents used, and is not particularly limitedinsofar as the reaction is not inhibited and the starting materials aredissolved to a certain degree, and preferable examples of the solventinclude ethers such as tetrahydrofuran, dioxane, dimethyxyethane anddiethylene glycol etc. The reaction temperature is preferably −78° C. toroom temperature, more preferably in the vicinity of 0° C.

wherein A and the ring B have the same meanings as defined above; and Meis a methyl group. N,N-dimethylformamide dimethylacetal is allowed toact on the active methylene of Compound (3) produced in ProductionMethod A, whereby 3-(dimethylamino)-2-propene-1-one compound (4) as anintermediate for production of the compound represented by the aboveformula (I) in this invention can be produced (step B1). This reactionis carried out preferably in the absence of a solvent, but the reactionmay be carried out after diluting with a solvent not inhibiting thereaction and dissolving the starting materials to a certain degree, forexample, N,N-dimethylformamide, tetrahydrofuran, dioxane, N-methylpyrrolidone, benzene, toluene etc. However, the solvent used herein isvaried depending on the starting materials, reagents etc. used, and isnot particularly limited. Usually, the reaction temperature ispreferably room temperature to 120° C., more preferably about 100° C.

wherein A, B and Me have the same meanings as defined above, and R¹represents a hydrogen atom, a morpholinyl group or a group representedby the formula —NR^(1a)R^(1b) (wherein R^(1a) and R^(1b) are the same asor different from each other and each represents a hydrogen atom, a C₁₋₆alkyl group, a C₁₋₆ acyl group, a phenyl group or a C₁₋₆ alkylsulfonylgroup). Formamidine or guanidine derivative (5) is reacted in thepresence of a base with the 3-(dimethylamino)-2-propene-1-one compound(4) obtained in Production Method B, whereby Compound (6) in thisinvention can be produced (step C1). The guanine derivative (5) used isnot only easily commercially available but can also be produced by aknown method described in e.g. J. Org. Chem., 57, 2497-2502 (1992) orits analogous method. The base used is varied depending on the startingmaterials, reagents, solvent etc. used, and is not particularly limitedinsofar as the reaction is not inhibited, and preferable examplesinclude alkali metal carbonates (for example, potassium carbonate,sodium carbonate, etc.), alkali metal alkoxides (for example, sodiummethoxide, sodium ethoxide, potassium tert-butoxide etc.), etc. Thisreaction is carried out preferably in a solvent not inhibiting thereaction and dissolving the starting materials and base to a certaindegree, for example in N,N-dimethylformamide, N-methylpyrrolidone,dimethylsulfoxide, methanol, ethanol etc., but it varies depending onthe starting materials, reagents etc. used, and is not particularlylimited. Usually, the reaction temperature is preferably roomtemperature to 120° C., more preferably about 70° C.

wherein A, ring B, and R¹ have the same meanings as defined above.Compound (9) in this invention can be obtained by dehydrationcondensation of aryl aldehyde with aryl acetonitrile (7) in the presenceof a base, to produce 2,3-biaryl-2-propenenitrile (8) (step D1), thenallowing formanidine or guanidine derivative to react on the nitrilecompound (8) in the presence of a base and converting the product intoan aromatic derivative by an oxidizing agent (step D2).

Step D1 The base used in step D1 is varied depending on the startingmaterials, reagents, solvent etc. used, and is not particularly limitedinsofar as the reaction is not inhibited, and preferable examplesinclude alkali metal alkoxides (for example, sodium methoxide, sodiumethoxide, potassium tert-butoxide etc.), alkali metal carbonates (forexample, potassium carbonate, sodium carbonate, etc.). The solvent usedin the reaction is varied depending on the starting materials, reagents,etc. used, and is not particularly limited insofar as it dissolves thestarting materials to a certain degree without inhibiting the reaction,and preferable examples include ethanol, methanol, tetrahydrofuran,dichloromethane, chloroform, N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide and mixed solvents thereof. The reactionis carried out usually at 0 to 120° C.

Step D2 The guanidine derivative used in step D2 is not only easilycommercially available but can also be produced by a known methoddescribed in e.g. J. Org. Chem., 57, 2497-2502 (1992) or its analogousmethod. The base used is varied depending on the starting materials,reagents, solvent, etc. used, and is not particularly limited insofar asthe reaction is not inhibited, and preferable examples include alkalimetal alkoxides (for example, sodium methoxide, sodium ethoxide,potassium tert-butoxide, etc.), alkali metal carbonates (for example,potassium carbonate, sodium carbonate, etc.), etc. The oxidizing agentused is also varied depending on the starting materials, reagents,solvent, etc. used, and is not particularly limited insofar as thereaction is not inhibited, and preferable examples include manganesecompounds (for example, activated manganese dioxide, etc.), quinones(for example, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, etc.), sulfur,etc. The solvent used is varied depending on the starting materials,reagents, etc. used, and is not particularly limited insofar as itdissolves the starting materials to a certain degree without inhibitingthe reaction, and preferable examples include ethanol, methanol,tetrahydrofuran, dichloromethane, chloroform, N,N-dimethylformamide,N-methyl pyrrolidone, dimethyl sulfoxide and mixed solvents thereof. Thereaction temperature in step D2 is usually 0 to 120° C.

In the step D1, the formamidine or guanidine derivative may becoexistent from the start in the reaction, and the2,3-biaryl-2-propenenitrile (8) can be converted without isolation intoits corresponding aromatic compound by an oxidizing agent, to producethe pyrimidine derivative (9) in the invention.

wherein A and the ring B have the same meanings as defined above, and R³represents a hydrogen atom or a C₁₋₆ alkyl group. Step E1 is a stepwhere a carboxylic anhydride is allowed to act on Compound (10) underacidic conditions to acrylate the amino group thereof, whereby the acylderivative (11) according to the present invention is produced. Thestarting compound (10) can be produced in Production Method C above, andcorresponds to Compound (6) wherein R¹ is an amino group. Step E1 iscarried out preferably in the absence of a solvent, but may be conductedafter dilution with a solvent. Such a solvent is varied depending on thestarting material, reagents, etc. used, and is not particularly limitedinsofar as it dissolves the staring materials without inhibiting thereaction, and preferable examples are N,N-dimethylformamide,tetrahydrofuran, dioxane, N-methyl pyrrolidone, benzene, toluene, etc.The acid used is varied depending on the starting materials, reagents,solvent, etc. used, and is not particularly limited insofar as it doesnot inhibit the reaction, and a preferable acid is a mineral acid suchas conc. sulfuric acid. The reaction temperature is preferably roomtemperature to 120° C., more preferably about 90° C.

wherein A and the ring B have the same meanings as defined above, and R⁴represents a hydrogen atom or a C₁₋₆ alkyl group. The sulfonamidederivative (13) in this invention can be produced by allowing sulfonylchloride under basic conditions to act on Compound (12) as the startingmaterial (that is, Compound (11) wherein R³ is a methyl group) which canbe produced by Production Method E above, thus sulfonylating Compound(12), and then removing the acyl group under acidic conditions (stepF1). The base used in the sulfonylation reaction is varied depending onthe starting materials, reagents, solvent, etc. used, and is notparticularly limited insofar as the reaction is not inhibited, andpreferable examples are sodium hydride, etc. The solvent used in thesulfonylation is varied depending on the starting materials, reagents,etc. used, and is not particularly limited insofar as it dissolves thestarting materials to a certain degree without inhibiting the reaction,and preferable examples include ethers such as tetrahydrofuran, dioxane,dimethyxyethane and diethyleneglycol. The reaction temperature ispreferably −10° C. to room temperature. The acid used in thede-acetylation reaction in step F1 is varied depending on the startingmaterials, reagents, solvent etc. used, and is not particularly limitedinsofar as the reaction is not inhibited, and a preferable example ishydrochloric acid or the like. The solvent used in the reaction isvaried depending on the starting materials, reagents, etc. used, and isnot particularly limited in so far as it dissolves the startingmaterials to a certain degree and is miscible with water to a certaindegree without inhibiting the reaction, and a preferable example is amixed solvent of an ether (for example, tetrahydrofuran) and water. Thereaction temperature is preferably room temperature to 100° C.

wherein A and R¹ have the same meanings as defined above. The compoundrepresented by the formula (II) in the present invention can beproduced, for example, in the step G1. Compound (14) as the startingmaterial can be produced by Production Method C above. The pyridonederivative (15) according to the present invention can be produced byhydrolyzing the according (14) under acidic conditions. The acid used isvaried depending on the starting materials, reagents, solvent, etc.used, and is not particularly limited insofar as the reaction is notinhibited, and preferable examples are hydrochloric acid, hydrobromicacid, sulfuric acid, etc. This reaction is carried out preferably inwater, and the reaction temperature is usually room temperature to about120° C., preferably 100° C.

where in A and R¹ have the same meanings as defined above. Compound (16)according to the present invention can be produced by allowing ammoniato act on Compound (14) which can be produced by Production Method Cabove to substitute the fluorine atom by an amino group (step H1). Anammonia gas saturated in a suitable solvent such as ethanol is used asthe reagent in this reaction. In this reaction, it is preferable thatthe reaction solution is sealed in e.g. an autoclave and heated to about150° C.

The starting compound in production of Compound (I) or (II) in thepresent invention may be in the form of a salt or a hydrate and is notparticularly limited insofar as the reaction is not inhibited. Further,when Compound (I) or (II) in the invention is obtained in a free form,it can be converted in a usual manner into a salt form which Compound(I) or (III) may form. Further, the resultant isomers (for example,geometric isomer, optical isomer based on asymmetric carbon,stereoisomer, tautomer etc.) of Compound (I) or (II) of the presentinvention can be purified and isolated by usual separating means, forexample recrystallization, diastereomer salt method, enzymefractionation method, and various kinds of chromatography (for example,thin-layer chromatography, column chromatography, gas chromatographyetc.).

Production Examples of the Pharmaceutical Composition or Compound of thePresent Invention

The pharmaceutical composition of the invention can be manufactured by aconventional method, and preferable preparation forms include tablets,powders, fine granules, granules, coated tablets, capsules, syrups,troches, inhalations, suppositories, injections, ointments, eyeointments, eye drops, nose drops, ear drops, poultices, lotions and thelike. Ordinarily used fillers, binders, disintegrating agents,lubricants, coloring agents, flavoring agents, and as necessity,stabilizers, emulsifiers, absorption promoters, surfactants, pHadjusters, preservatives and antioxidants can be used in pharmaceuticalmanufacturing, and ingredients used generally as starting materials forpharmaceutical preparations can be blended in a usual manner formanufacturing. These ingredients include e.g. (1) animal and vegetableoils such as soybean oil, tallow and synthetic glyceride; (2)hydrocarbons such as liquid paraffin, squalane and solid paraffin; (3)ester oils such as octyldodecyl myristate and isopropyl myristate; (4)higher alcohols such as cetostearyl alcohol and behenyl alcohol; (5)silicon resin; (6) silicon oil; (7) surfactants such as polyoxyethylenefatty ester, sorbitan fatty ester, glycerin fatty ester, polyoxyethylenesorbitan fatty ester, polyoxyethylene hardened castor oil andpolyoxyethylene polyoxypropylene block copolymer; (8) water-solublepolymers such as hydroethyl cellulose, polyacrylic acid, carboxyvinylpolymer, polyethylene glycol, polyvinyl pyrrolidone and methylcellulose; (9) lower alcohols such as ethanol and isopropanol; (10)polyvalent alcohols such as glycerin, propylene glycol, dipropyleneglycol and sorbitol; (11) sugars such as glucose and sucrose; (12)inorganic powder such as silicic anhydride, aluminum magnesium silicateand aluminum silicate; and (13) pure water.

1) The fillers include e.g. lactose, corn starch, white sugar, glucose,mannitol, sorbitol, crystalline cellulose, silicon dioxide etc.; 2) thebinders include e.g. polyvinyl alcohol, polyvinyl ether, methylcellulose, ethyl cellulose, arabic gum, tragacanth, gelatin, shellac,hydroxy propyl cellulose, hydroxy propylmethyl cellulose, polyvinylpyrrolidone, polypropylene glycol-polyoxyethylene block polymer,meglumine, calcium citrate, dextrin, pectin etc.; 3) the disintegratingagents include e.g. starch, agar, gelatin powder, crystalline cellulose,calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin,carboxymethyl cellulose calciumetc.; 4) the lubricants include e.g.magnesium stearate, talc, polyethyleneglycol, silica, hardened vegetableoil etc.; 5) the coloring agents include e.g. those coloring agentsapproved to be added to pharmaceutical preparations; 6) the flavoringagents include cocoa powder, menthol, aromatic powder, peppermint oil,borneol, cinnamon powder etc.; and 7) the antioxidants include thoseapproved to be added to pharmaceutical preparations, such as ascorbicacid and α-tocopherol.

1) The oral preparation is produced by mixing the active ingredient withfillers and if necessary with a binder, a disintegrating agent, alubricant, a coloring agent, a flavoring agent etc., and then forming itin a usual manner into powders, fine granules, granules, tablets, coatedtablets, capsules, etc. 2) The tablets and granules may be coated with asugar or gelatin coating or if necessary with another suitable coating.3) The liquid preparations such as syrups, injections and eye drops areprepared by mixing the active agent with a pH adjuster, a solubilizerand an isotonizing agent etc., and with a solubilizing aid, astabilizer, a buffer, a suspension agent, an antioxidant etc. ifnecessary, followed by forming it into a preparation in a usual manner.The liquid preparation may be formed into a freeze-dried product and theinjection can be administered intravenously, subcutaneously orintramuscularly. Preferable examples of the suspension agent includemethyl cellulose, Polysorbate 80, hydroxyethyl cellulose, arabic gum,tragacanth powder, sodium carboxymethyl cellulose, polyoxyethylenesorbitan monolaurate etc.; preferable examples of the solubilizing aidinclude polyoxyethylene hardened castor oil, Polysorbate 80,nicotinamide, polyoxyethylene sorbitan monolaurate etc.; preferableexamples of the stabilizer include sodium sulfite, sodium metasulfite,ether etc.; preferable examples of the preservative include methylp-oxybenzoate, ethyl p-oxybenzoate, sorbic acid, phenol, cresol,chlorocresol etc. 4) The agent for external application can be producedin any conventional method. That is, the starting base material can makeuse of various starting materials ordinarily used in pharmaceuticalpreparations, non-pharmaceutical preparations, cosmetics, etc. Forexample, the material includes animal and vegetable oils, mineral oil,ester oil, waxes, higher alcohols, fatty acids, silicon oil,surfactants, phospholipids, alcohols, polyvalent alcohols, water-solublepolymers, clay minerals, pure water etc. If necessary, a pH adjuster, anantioxidant, a chelating agent, a preservative, a coloring agent, aperfume etc. can further be added. Further, ingredients having adifferentiation-inducing action, a blood-stream promoting agent,asterilizer, an antiinflammatory agent, a cell activator, vitamins,amino acids, a humectant, a keratin solubilizer etc. can also beincorporated as necessity.

Although the dose of the pharmaceutical composition or compoundaccording to the present invention is varied depending on severity ofsymptoms, age, sex, body weight, administration form, type of salt,chemical sensitivity, specific type of disease etc., it is given dailyin one portion or in divided portions into an adult in a dose of usuallyabout 30 ”g to 10 g, preferably 100 μg to 5 g, more preferably 100 μg to100 mg for oral administration, or about 30 μg to 1 g, preferably 100 μgto 500 mg, more preferably 100 μg to 30 mg for injection.

Accordingly to this invention, there can be provided a novelpharmaceutical composition promoting defecation. Thedefecation-promoting agent according to the present invention is usefulas a pharmaceutical preparation promoting physiological defecation.According to the present invention, there can also be provided a novelpyrimidine compound and a salt thereof. The compound or a salt thereofis useful as a pharmaceutical preparation exhibiting an excellentantagonistic action on adenosine A₂ receptor, particularly on A_(2b)receptor, and simultaneously promoting defecation. Accordingly, thedefecation-promoting pharmaceutical composition according to the presentinvention and the compound of the present invention are useful as anagent for treating, preventing or improving various kinds ofconstipation, for example functional constipation (acute constipationand various kinds of chronic constipation (for example, atonicconstipation, spastic constipation, dyschezia, rectal constipation,chemically inducible constipation etc.)), organic constipation,enteroparalytic ileus, IBS, constipation accompanying IBS, constipationaccompanying congenital digestive tract dysfunction, constipationaccompanying ileus etc. Further, use of the defecation-promoting agentaccording to the present invention as a pharmaceutical preparation isnot limited to the treatment, prevention or improvement of various kindsof constipation, but it is also useful as a chemical for evacuatingintestinal tracts at the time of examination of digestive tracts orbefore and after an operation, as an aid for defecation after anoperation, as a chemical for promotion of defecation after administeringa contrast medium, and as a defecation-promoting agent when the patientis hypertensive or has a dangerous of cerebral apoplexy, cerebralinfarction, cardiac infarction, etc.

EXAMPLES

As examples of the active ingredient in the pharmaceutical compositionpromoting defecation according to the present invention, the best modeexcept for the previously described known compounds is described. Thepreviously described, known compounds and the following examples aredescribed merely for illustrative purposes, and not intended to limitthe compounds as the active ingredient in the pharmaceutical compositionof the invention. Compounds not described specifically in thespecification but having an A₂ receptor antagonism, particularly anA_(2b) receptor antagonism and a salt thereof, are useful as the activeingredient in the defecation-promoting pharmaceutical compositionaccording to the present invention, and such pharmaceutical compositionsare included in the claims in this specification.

Reference Example 1 3-(3-Fluorophenyl)-2-(4-pyridyl)-2-propene nitrile

After sodium (3.0 g, 130 mmol) was dissolved in ethanol (150 mL),4-pyridyl acetonitrile hydrochloride (33 g, 121 mmol) was added theretoand stirred at room temperature. After 10 minutes, 3-fluorobenzaldehyde(8 g, 65 mmol) was added thereto and stirred as such for30 minutes. Theresulting precipitates were collected by filtration and washed with asmall amount of water, to give the title compound (8.2 g, 56%) as acolorless solid.

¹HNMR (400 MHz, DMSO-d₆) δ ppm; 7.40-7.46 (1H, m), 7.61-7.68 (1H, m),7.75 (2H, dd, J=1.6, 4.4 Hz), 7.77-7.86 (2H, m), 8.37 (1H, s), 8.73 (2H,dd, J=1.6, 4.4 Hz).

Reference Example 2 1-(2-Furyl)-2-(4-pyridyl)-1-ethanone

Lithium bis(trimethylsilyl)amide (100 mL, 100 mmol) was added dropwiseover 1 hour to a solution of 4-picoline (4.6 g, 49.4 mmol) and ethyl2-furancarboxylate (7.7 g, 54.9 mmol) in tetrahydrofuran (40 mL) at 0°C. in a nitrogen atmosphere, followed by stirring as such for 2 hours.Hexane (140 mL) was added to the reaction solution, and the resultingcrystals were collected by filtration. The resulting crystals weredissolved in ethyl acetate and an aqueous saturated ammonium chloridesolution. The organic layer was washed with an aqueous saturatedammonium chloride solution (×2) and brine, dried over anhydrous sodiumsulfate, and concentrated. Hexane was added to the residue, and theresulting precipitates were collected by filtration and washed withhexane, to give the title compound (6.5 g, 70%) as a pale yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 4.26 (2H, s), 6.77 (1H, dd, J=2.0, 3.6Hz), 7.31 (2H, dd, J=1.6, 4.4 Hz), 7.65 (1H, dd, J=0.8, 3.6 Hz), 8.05(1H, dd, J=0.8, 2.0 Hz), 8.51 (2H, dd, J=1.6, 4.4 Hz).

Reference Example 33-(Dimethylamino)-1-(2-furyl)-2-(4-pyridyl)-2-propene-1-one

N,N-dimethylformamide dimethyl acetal (5 mL) was added to1-(2-furyl)-2-(4-pyridyl)-1-ethanone (2.0 g, 10.7 mmol) and stirred at100° C. for 2 hours. After cooling as it was, the reacton mixture wasdiluted with ethyl acetate and an aqueous saturated ammonium chloridesolution. The aqueous layer was extracted with ethyl acetate (×6). Thecombined organic layer was dried over anhydrous sodium sulfate andconcentrated, to give the title compound (2.5 g, 97%) as a reddish brownoil.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.80 (6H, br s), 6.53 (1H, br), 6.60(1H, br), 7.10 (2H, d, J=4.0 Hz), 7.65 (1H, br), 7.75 (1H, s), 8.44 (2H,d, J=4.0 Hz).

Example 1 6-(3-Flurophenyl)-5-(4-pyridyl)-2,4-pyrimidinediamine

After sodium (6.2 g, 268 mmol) was dissolved in ethanol (700 mL),3-(3-fluorophenyl)-2-(4-pyridyl)-2-propene nitrile (50 g, 223 mmol) andguanidine hydrochloride (25.6 g, 268 mmol) were added thereto in thisorder and heated under reflux for 4 hours. After cooling as it was, thesolvent was removed. Tetrahydrofuran (500 mL) was added to the residue,the insoluble matters were filtered off, and the filtrate wasconcentrated. A suspension of the residues and activated manganesedioxide (200 g) in chloroform (1000 mL) was heated under reflux for 2hours. After cooling as it was, the manganese dioxide was filtered offthrough Celite, and washed with tetrahydrofuran (500 mL×3) andmethanol-chloroform (1:1) (1000 mL×2). The collected filtrate wasconcentrated, and then methanol was added to the residue. The resultingprecipitates were collected by filtration, to give the title compound asa crude solid (14.6 g). The crude crystals were recrystallized frommethanol-chloroform, to give the title compound (12.4 g, 20 ) as acolorless solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.03 (2H, br s), 6.22 (2H, br s),6.90-7.00 (2H, m), 7.01-7.12 (1H, m), 7.08 (2H, d, J=5.6 Hz), 7.16-7.23(1H, m), 8.43 (2H, d, J=5.6 Hz) ; MS m/e (ESI) 282 (MH⁺).

Example 2 6-(2-Furyl)-5-(4-pyridyl)-2,4-pyrimidinediamine

After sodium (3.2 g, 139 mmol) was dissolved in anhydrous ethanol (200mL), 4-pyridyl acetonitrile hydrochloride (10.0 g, 64 mmol) and2-furaldehyde (6.1 mL, 73.6 mmol) and guanidine hydrochloride (7.0 g,73.3 mmol) were successively added thereto.

After stirring at room temperature for 1 hour, it was heated underreflux for 7 hours. After cooling as it was, the insoluble matters werefiltered off, washed with tetrahydrofuran, and the solvent was removedfrom the filtrate. Tetrahydrofuran (200 mL) and activated manganesedioxide (30.0 g) were added to the residue, followed by heating underreflux for 2.5 hours. After cooling as it was, the manganese dioxide wasfiltered through Celite, and washed with tetrahydrofuran. The collectedfiltrate was concentrated, and then methanol was added to the residues.The resulting precipitates were collected by filtration and washed withmethanol, to give the title compound (3.48 g, 21%) as a pale brownsolid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 5.88 (2H, br s), 6.15 (2H, br s), 6.18(1H, d, J=3.2 Hz), 6.38 (1H, dd, J=1.8, 3.2 Hz), 7.18 (2H, dd, J=1.4,4.4 Hz), 7.47-7.51 (1H, m), 8.59 (2H, dd, J=1.4, 4.4 Hz).

Example 3 4-(2-Furyl)-5-(4-pyridyl)-2-pyrimidinyl amine

A suspension of3-(dimethylamino)-1-(2-furyl)-2-(4-pyridyl)-2-propene-1-one (2.2 g, 9.08mmol), guanidine hydrochloride (2.6 g, 27.2 mmol) and potassiumcarbonate (7.5 g, 54.3 mmol) in N,N-dimethylformamide (20 mL) wasstirred at 70° C. for 12 hours. After cooling as it was, the reactionmixture was diluted with water. The resulting crystals were collected byfiltration and washed with water, to give the title compound (1.73 g,80%) as a pale yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.56 (1H, dd, J=1.6, 3.6 Hz), 6.68 (1H,dd, J=0.8, 3.6 Hz), 6.98 (2H, br s), 7.27 (2H, dd, J=1.6, 4.4 Hz), 7.67(1H, dd, J=0.8, 1.6 Hz), 8.22 (1H, s), 8.56 (2H, dd, J=1.6, 4.4 Hz)

MS m/e (ESI) 239 (MH⁺).

Example 4 4-(3-Fluorophenyl)-5-(4-pyridyl)-2-pyrimidinylamine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 7.04-7.07 (1H, m), 7.10 (2H, br s),7.12-7.18 (1H, m), 7.14 (2H, dd, J=1.6, 4.4 Hz), 7.20-7.26 (1H, m),7.32-7.38 (1H, m), 8.38 (1H, s), 8.45 (2H, dd, J=1.6, 4.4 Hz);

MS m/e (ESI) 267 (MH⁺).

Example 5 4-Phenyl-5-(4-pyridyl)-2-pyrimidinylamine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

¹H NMR (400 MHz, DMSO-d₆) δ d ppm; 7.04 (2H, br s), 7.10 (2H, d, J=5.4Hz), 7.28-7.41 (5H, m), 8.36 (1H, s), 8.42 (2H, d, J=5.4 Hz);

MS m/e (ESI) 249 (MH⁺).

Example 6 5-(4-Pyridyl)-4-(2-thienyl)-2-pyrimidinylamine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.70 (1H, dd, J=1.2, 3.8 Hz), 6.94 (1H,dd, J=3.8, 5.2 Hz), 6.97 (2H, br s), 7.37 (2H, dd, J=1.6, 4.4 Hz), 7.67(1H, dd, J=1.2, 5.2 Hz), 8.16 (1H, s), 8.61 (2H, dd, J=1.6, 4.4 Hz);

MS m/e (ESI) 255 (MH⁺).

Example 7 4-(2-Pyridyl)-5-(4-pyridyl)-2-pyrimidinylamine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 7.02 (2H, dd, J=1.6, 4.6 Hz), 7.09(2H,br s), 7.37-7.41 (1H, m), 7.71-7.75 (1H, m), 7.88-7.93 (1H, m),8.34-8.37 (1H, m), 8.37 (2H, dd, J=1.6, 4.6 Hz), 8.42 (1H, s);

MS m/e (ESI) 250 (MH⁺).

Example 8 4-(3-Fluorophenyl)-5-(4-pyridyl)pyrimidine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 7.08-7.15 (2H, m), 7.17 (2H, dd, J=1.6,4.4 Hz), 7.22-7.31 (2H, m), 8.64 (2H, dd, J=1.6, 4.4 Hz), 8.77 (1H, s),9.33 (1H, m);

MS m/e (ESI) 252 (MH⁺).

Example 9 4-(3-Fluorophenyl)-5-(2-fluoro-4-pyridyl)pyrimidine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (FAB) 270 (MH⁺).

Example 10 4-(3-Fluorophenyl)-5-(2-fluoro-4-pyridyl)-2-pyrimidinylamine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (FAB) 285 (MH⁺).

Example 11N-[4-(3-Fluorophenyl)-5-(4-pyridyl)-2-pyrimidinyl]-N,N-dimethylamine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (ESI) 295 (MH⁺).

Example 12N-[4-(3-Fluorophenyl)-5-(4-pyridyl)-2-pyrimidinyl]-N-methylamine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (ESI) 281 (MH⁺).

Example 13 4-[4-(3-Fluorophenyl)-5-(4-pyridyl)-2-pyrimidinyl]morpholine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (ESI) 337 (MH⁺).

Example 14N-[4-(3-Fluorophenyl)-5-(2-fluoro-4-pyridyl)-2-pyrimidinyl]-N-methylamine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (FAB) 299 (MH⁺).

Example 154-[4-(3-Fluorophenyl)-2-(methylamino)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone

A mixture ofN-[4-(3-fluorophenyl)-5-(2-fluoro-4-pyridyl)-2-pyrimidinyl]-N-methylamine(30 mg, 0.101 mmol) and 6 N hydrochloric acid (3 mL) was heated underreflux for 40 minutes. The reaction solution was cooled as it was, andthen washed with ethyl acetate. The aqueous layer was neutralized with 5N aqueous sodium hydroxide, and then extracted with ethyl acetate, driedover anhydrous sodium sulfate and concentrated. The residue wassuspended in diethyl ether, and then the resulting solid was collectedby filtration and washed with diethyl ether, to give the title compound(20 mg, 67%).

MS m/e (FAB) 297 (MH⁺).

Example 16N-Ethyl-N-[4-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinyl]amine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (FAB) 295 (MH⁺).

Example 17 N1-[4-(3-Fluorophenyl)-5-(4-pyridyl)-2-pyrimidinyl]acetamide

A mixture of 4-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinylamine (200mg, 0.751 mmol), acetic anhydride (6 mL) and conc. sulfuric acid (4drops) was stirred at 90° C. for 16 hours. After cooling as it was, thereaction solution was diluted with ethyl acetate, water and a saturatedaqueous sodium bicarbonate solution. The organic layer was washed withsaturated sodium bicarbonate (×2) and brine, and then dried overanhydrous sodium sulfate and concentrated. The residue was suspended indiethyl ether, and then the resulting solid was collected by filtrationand washed with diethyl ether, to give the title compound (126 mg, 54%)

MS m/e (FAB) 309 (MH⁺).

Example 18N1-[4-(3-Fluorophenyl)-5-(4-pyridyl)-2-pyrimidinyl]-N1-methylacetamide

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3, Example 3 andExample 17.

MS m/e (FAB) 323 (MH⁺).

Example 19N1-[4-(3-Fluorophenyl)-5-(4-pyridyl)-2-pyrimidinyl]propanamide

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3, Example 3 andExample 17.

MS m/e (FAB) 323 (MH⁺).

Example 20 N1-[4-(3-Fluorophenyl)-5-(4-pyridyl)-2-pyrimidinyl]butanamide

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3, Example 3 andExample 17.

MS m/e (FAB) 337 (MH⁺).

Example 21N1-[4-(3-Fluorophenyl)-5-(4-pyridyl)-2-pyrimidinyl]-N1-methylpropanamide

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3, Example 3 andExample 17.

MS m/e (FAB) 337 (MH⁺).

Example 22 4-(3-Fluorophenyl)-5-(2-methyl-4-pyridyl)-2-pyrimidinylamine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (FAB) 281 (MH⁺).

Example 23N1-Ethyl-N1-[4-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinyl]propanamide

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3, Example 3 andExample 17.

MS m/e (FAB) 351 (MH⁺).

Example 24

N1-[4-(3-Fluorophenyl)-5-(2-fluoro-4-pyridyl)-2-pyrimidinyl]propanamide

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3, Example 3 andExample 17.

MS m/e (FAB) 341 (MH⁺).

Example 25N1-[4-(3-Fluorophenyl)-5-(2-methyl-4-pyridinyl)-2-pyrimidinyl]propanamide

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3, Example 3 andExample 17.

MS m/e (FAB) 337 (MH⁺).

Example 264-[2-Amino-4-(3-fluorophenyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3, Example 3 andExample 15.

MS m/e (FAB) 283 (MH⁺).

Example 27N-Ethyl-N-[4-(3-fluorophenyl)-5-(2-fluoro-4-pyridyl)-2-pyrimidinyl]amine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (FAB) 313 (MH⁺).

Example 284-[2-(Ethylamino)-4-(3-fluorophenyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3, Example 3 andExample 15.

MS m/e (FAB) 311 (MH⁺).

Example 29N-[4-(3-Fluorophenyl)-5-(4-pyridyl)-2-pyrimidinyl]-N-propylamine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (ESI) 309 (MH⁺).

Example 30N-[4-(3-Fluorophenyl)-5-(4-pyridyl)-2-pyrimidinyl]-N-phenylamine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (ESI) 343 (MH⁺).

Example 31N-Ethyl-N-[4-(3-fluorophenyl)-5-(2-methyl-4-pyridyl)-2-pyrimidinyl]amine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (ESI) 309 (MH⁺).

Example 325-(2,6-Dimethyl-4-pyridyl)-4-(3-fluorophenyl)-2-pyrimidinylamine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (ESI) 295 (MH⁺).

Example 33N-[5-(2,6-Dimethyl-4-pyridyl)-4-(3-fluorophenyl)-2-pyrimidinyl]-N-ethylamine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (ESI) 323 (MH⁺).

Example 34 4-(3-Fluorophenyl)-5-(3-methyl-4-pyridyl)-2-pyrimidinylamine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (FAB) 281 (MH⁺).

Example 35 5-(3-Ethyl-4-pyridyl)-4-(3-fluorophenyl)-2-pyrimidinylamine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (FAB) 295 (MH⁺).

Example 36 5-(2-Amino-4-pyridyl)-4-(3-fluorophenyl)-2-pyrimidinylamine

A mixture of4-(3-fluorophenyl)-5-(2-fluoro-4-pyridyl)-2-pyrimidinylamine (100 mg,0.352 mmol) and ammonia/ethanol (ethanol saturated with an ammonia gasunder ice-cooling) (20 mL) was sealed in a test tube and stirred at 150°C. for 2 weeks. After cooling as it was, the reaction solution wasconcentrated. The residue was dissolved by adding ethyl acetate andwater thereto. The organic layer was washed with water and brine, andthen dried over anhydrous sodium sulfate and concentrated. The residuewas purified by TLC plate (eluting solvent:dichloromethane/methanol=10/1), to give the title compound (12 mg, 12%)

MS m/e (FAB) 282 (MH⁺).

Example 37N4-Methyl-6-(3-fluorophenyl)-5-(4-pyridyl)-2,4-pyrimidinediamine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (ESI) 296 (MH⁺).

Example 38N4,N4-Dimethyl-6-(3-fluorophenyl)-5-(4-pyridyl)-2,4-pyrimidinediamine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (ESI) 310 (MH⁺).

Example 39 N-Ethyl-N-[4-(2-furyl)-5-(4-pyridyl)-2-pyrimidinyl]amine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (ESI) 267 (MH⁺).

Example 40N-Ethyl-N-[4-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinyl]amine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (ESI) 310 (MH⁺).

Example 41 N-Ethyl-N-[4-phenyl-5-(4-pyridyl)-2-pyrimidinyl]amine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (ESI) 277 (MH⁺).

Example 42 N-Ethyl-N-[5-(4-pyridyl)-4-(2-thienyl)-2-pyrimidinyl]amine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (ESI) 283 (MH⁺).

Example 43 5-(3-Ethyl-4-pyridyl)-4-(2-furyl)-2-pyrimidinylamine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (ESI) 267 (MH⁺).

Example 44N-Ethyl-N-[5-(3-ethyl-4-pyridyl)-4-(2-furyl)-2-pyrimidinyl]amine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (ESI) 295 (MH⁺).

Example 454-(2,5-Dimethyl-3-furyl)-5-(3-ethyl-4-pyridyl)-2-pyrimidinylamine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (ESI) 267 (MH⁺).

Example 46N-[4-(2,5-Dimethyl-3-furyl)-5-(3-ethyl-4-pyridyl)-2-pyrimidinyl]-N-ethylamine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (ESI) 295 (MH⁺).

Example 475-(2,6-Dimethyl-4-pyridyl)-6-(3-fluorophenyl)-2,4-pyrimidinediamine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (ESI) 310 (MH⁺).

Example 48 4-(3-Methyl-2-furyl)-5-(4-pyridyl)-2-pyrimidinylamine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (ESI) 253 (MH⁺).

Example 49N-[4-(3-Fluorpphenyl)-5-(4-pyridyl)-2-pyrimidinyl]methanesulfonamide

60% oily sodium hydride (20 mg, 0.500 mmol) was added to a solution ofN1-[4-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinyl]acetamide (100 mg,0.324 mmol) in tetrahydrofuran (10 mL) under ice-cooling in a nitrogenatmosphere. After stirring the reaction solution as it was for 20minutes, methanesulfonyl chloride (30 μL, 0.388 mmol) was added dropwisethereto and stirred at room temperature. After 1 hour, 60% oily sodiumhydride (20 mg, 0.500 mmol) and methanesulfonyl chloride (30 μL, 0.388mmol) were additionally added thereto under ice-cooling, and furtherstirred at room temperature for 1 hour. The reaction solution wasdiluted with ethyl acetate and a saturated aqueous ammonium chloridesolution. The organic layer was washed with a saturated aqueous ammoniumchloride solution, a saturated aqueous sodium bicarbonate solution and asaturated aqueous ammonium chloride solution, and then dried overanhydrous sodium sulfate and concentrated. The residues were purified byTLC plate (eluting solvent: dichloromethane/methanol=10/1), to give astarting sulfonamide compound (70 mg). To the product were addedtetrahydrofuran (10 mL) and 1 N hydrochloric acid (1 mL), followed byheating under reflux for 1 hour. After cooling as it was, the reactionsolution was concentrated. The residue was suspended in diethyl ether,and then the resulting solid was collected by filtration and washed withdiethyl ether, to give the title compound (68 mg, 55%) as hydrochloride.

MS m/e (ESI) 345 (MH⁺).

Example 50 4,5-Di(4-pyridyl)-2-pyrimidinylamine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (ESI) 250 (MH⁺).

Example 51 4-(4-Methoxyphenyl)-5-(4-pyridyl)-2-pyrimidinylamine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (ESI) 279 (MH⁺).

Example 52 4-(3,4-Dimethoxyphenyl)-5-(4-pyridyl)-2-pyrimidinylamine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (ESI) 309 (MH⁺).

Example 53 4-[2-Amino-5-(4-pyridyl)-4-pyrimidinyl]phenol

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (ESI) 265 (MH⁺).

Example 54 Methyl 3-[2-amino-5-(4-pyridyl)-4-pyrimidinyl]benzoate

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (ESI) 307 (MH⁺).

Example 55N4,N4-Dimethyl-6-(2-furyl)-5-(4-pyridyl)-2,4-pyrimidinediamine

The title compound was synthesized in an identical or analogous methodto that of Reference Example 2, Reference Example 3 and Example 3.

MS m/e (ESI) 282 (MH⁺) TABLE 9

Ex. No. a b c d 1 —NH₂ 3-F-Ph 4-Py —NH₂ 2 —NH₂ 2-Furyl 4-Py —NH₂ 3 —NH₂2-Furyl 4-Py —H 4 —NH₂ 3-F-Ph 4-Py —H 5 —NH₂ Ph 4-Py —H 6 —NH₂ 2-Thienyl4-Py —H 7 —NH₂ 2-Py 4-Py —H 8 —H 3-F-Ph 4-Py —H 9 —H 3-F-Ph 2-F-4-Py —H10 —NH₂ 3-F-Ph 2-F-4-Py —H 11 —NMe2 3-F-Ph 4-Py —H 12 —NHMe 3-F-Ph 4-Py—H 13 -(4-Morpholinyl) 3-F-Ph 4-Py —H 14 —NHMe 3-F-Ph 2-F-4-Py —H 15—NHMe 3-F-Ph 1,2-2H-2-pyridinone-4-yl —H 16 —NHEt 3-F-Ph 4-Py —H 17—NHCOMe 3-F-Ph 4-Py —H 18 —N(Me)COMe 3-F-Ph 4-Py —H 19 —NHCOEt 3-F-Ph4-Py —H 20 —NHCOn-Pr 3-F-Ph 4-Py —H 21 —N(Me)COEt 3-F-Ph 4-Py —H 22 —NH₂3-F-Ph 2-Me-4-Py —H 23 —N(Et)COEt 3-F-Ph 4-Py —H 24 —NHCOEt 3-F-Ph2-F-4-Py —H 25 —NHCOEt 3-F-Ph 2-Me-4-Py —H 26 —NH₂ 3-F-Ph1,2-2H-2-pyridinone-4-yl —H 27 —NHEt 3-F-Ph 2-F-4-Py —H 28 —NHEt 3-F-Ph1,2-2H-2-pyridinone-4-yl —H 29 —NHn-Pr 3-F-Ph 4-Py —H 30 —NHPh 3-F-Ph4-Py —H 31 —NHEt 3-F-Ph 2-Me-4-Py —H 32 —NH₂ 3-F-Ph 2,6-DiMe-4-Py —H 33—NHEt 3-F-Ph 2,6-DiMe-4-Py —H 34 —NH₂ 3-F-Ph 3-Me-4-Py —H 35 —NH₂ 3-F-Ph3-Et-4-Py —H 36 —NH₂ 3-F-Ph 2-NH₂-4-Py —H 37 —NH₂ 3-F-Ph 4-Py —NHMe 38—NH₂ 3-F-Ph 4-Py —NMe₂ 39 —NHEt 2-Furyl 4-Py —H 40 —NHEt 3-F-Ph 4-Py —H41 —NHEt Ph 4-Py —H 42 —NHEt 2-Thienyl 4-Py —H 43 —NH₂ 2-Furyl 3-Et-4-Py—H 44 —NHEt 2-Furyl 3-Et-4-Py —H 45 —NH₂ 2,5-Dimethyl-3-furyl 3-Et-4-Py—H 46 —NHEt 2,5-Dimethyl-3-furyl 3-Et-4-Py —H 47 —NH₂ 3-F-Ph2,6-DiMe-4-Py —NH₂ 48 —NH₂ 3-Methyl-2-furyl 4-Py —H 49 —NHSO₂Me 3-F-Ph4-Py —H 50 —NH₂ 4-Py 4-Py —H 51 —NH₂ 4-MeO-Ph 4-Py —H 52 —NH₂3,4-DiMeO-Ph 4-Py —H 53 —NH₂ 4-OH-Ph 4-Py —H 54 —NH₂3-Methoxycarbonyl-Ph 4-Py —H 55 —NH₂ 2-Furyl 4-Py —NMe₂In the table above, Ph means a phenyl group; Py, pyridyl group; Me,methyl group; Et, ethyl group; DiMe, dimethyl group; n-Pr, n-propylgroup; F, fluorine atom (fluoro); MeO, methoxy group; DiMeO, dimethoxygroup; OH, hydroxyl group; and 2H, dihydro, resepectively.Evaluation of Defecation-Promoting Action

The defecation-promoting action of the adenosine A_(2b)receptor-inhibiting compound which was identified by measuring thebinding ability and inhibitory ability thereof to the adenosine receptorin the above method, a salt thereof, a hydrate of them, or apharmaceutical composition containing it can be evaluated on the basisof the method described in this specification.

That is, SD IGS rats (6-to 7-weeks-old, from Charles River) were placedin cages (3 animals/cage) and preliminarily allowed food and water adlibitum and raised for 1 week. On the day of the experiment, theirweight was measured, a water-absorbing sheet was placed below each cage,and the animals were fasted but allowed water ad libitum throughout theexperiment. Thee hours after fasting was initiated, the fecal pelletswere recovered from each cage and observed for abnormality before theexperiment, and then the compound suspended in 0.5% (w/v) methylcellulose (MC) was orally administered in a dose of 5 ml/kg. On onehand, 0.5% (w/v) MC only was orally given to the control group. Afteradministration of the compound, the rats were returned to the cageprovided with a new water-absorbing sheet, and 180 minutes after theadministration, the fecal pellets on the water-absorbing sheet wererecovered from each cage, and the external appearance was observed, andthe number of fecal pellets was counted. The number of fecal pellets isexpressed per each cage.

Both compounds (I) and (II) in the invention exhibited an excellentadenosine A₂ receptor antagonism, and exhibited an excellent antagonismparticularly to an adenosine A_(2b) receptor. Further, both compounds(I) and (II) exhibited an excellent defecation-promoting action. Thedefecation-promoting action of the title compound in Example 1 is shownbelow. The defecation-promoting action of the title compound in Example3 is as shown in the above tables. TABLE 10 The number of Compound Dosefecal pellets/3 rats Control —  4.67 ± 1.26 Example 1  3 mg/kg 14.83 ±1.82 ** 10 mg/kg 23.17 ± 2.94 ***The number of cages; n = 6 cages/group (18 rats/group)** p < 0.01,*** p < 0.001,NS; not significant, Dunnett's test

1. A defecation-promoting agent comprising a compound having anadenosine A₂ receptor antagonism or a salt thereof.
 2. A compoundrepresented by the formula:

wherein A represents a phenyl group, pyridyl group, thienyl group orfuryl group which may be substituted with one or two groups selectedfrom a halogen atom, a hydroxyl group, a C₁₋₆alkyl group, a C₁₋₆alkoxygroup and a C₁₋₆alkoxy-carbonyl group; B may be substituted with one ormore groups selected from a halogen atom, hydroxyl group, a C₁₋₆ alkylgroup and amino group; R¹ represents a hydrogen atom, a morpholinylgroup or a group represented by the formula —NR^(1a)R^(1b), whereinR^(1a) and R^(1b) are the same as or different from each other and eachrepresents a hydrogen atom, a C₁₋₆ alkyl group, a C₁₋₆ acyl group, aphenyl group or a C₁₋₆ alkylsulfonyl group; and R² represents a hydrogenatom or a group represented by the formula —NR^(2a)R^(2b), whereinR^(2a) and R^(2b) are the same as or different from each other and eachrepresents a hydrogen atom or a C₁₆ alkyl group, provided that, in theabove definition, the cases (i) where, A is a 4-fluorophenyl group; B isa 4-pyridyl group; R¹ is an amino group; and R² is a hydrogen atom, and(ii) where, A is a 4-fluorophenyl group; B is a 4-pyridyl group, R¹ isan acetamide group; and R² is a hydrogen atom are excluded, or a saltthereof.
 3. A pharmaceutical composition comprising a pharmacologicallyeffective amount of the compound according to claim 2, or apharmacologically acceptable salt of thereof and a pharmaceuticallyacceptable carrier.
 4. A method for promotion of defecation, byadministering a pharmacologically effective amount of the compounddescribed in claim 2 or a salt thereof to a patient.
 5. A method fortreating or improving constipation, by administering a pharmacologicallyeffective amount of the compound described in claim 2 or a salt thereofto a patient.
 6. The method according to claim 3, wherein the patient issuffering from a disease selected from the group consisting ofconstipation, functional constipation, spastic constipation, atonicconstipation, irritable bowel syndrome, constipation accompanyingirritable bowel syndrome, organic constipation, constipationaccompanying enteroparalytic ileus, constipation accompanying congenitaldigestive tract dysfunction and constipation accompanying ileus, orcombinations thereof.
 7. The method according to claim 4, wherein thepatient is suffering from a disease selected from the group consistingof constipation, functional constipation, spastic constipation, atonicconstipation, irritable bowel syndrome, constipation accompanyingirritable bowel syndrome, organic constipation, constipationaccompanying enteroparalytic ileus, constipation accompanying congenitaldigestive tract dysfunction and constipation accompanying ileus, orcombinations thereof.